Ford, A.M.
Colman, S.
Greaves, M.
(2023). Covert pre-leukaemic clones in healthy co-twins of patients with childhood acute lymphoblastic leukaemia. Leukemia,
Vol.37
(1),
pp. 47-52.
full text
Pombo-de-Oliveira, M.S.
EMiLI Study Group,
Petridou, E.T.
Karalexi, M.A.
Junqueira, M.E.
Braga, F.H.
Bouzas, L.F.
Murra, G.R.
Lopes, L.F.
Ntzani, E.
Greaves, M.
(2023). The Interplay of Cesarean-Section Delivery and First-Birth Order as Risk Factors in Acute Lymphoblastic Leukemia. Cancer epidemiol biomarkers prev,
Vol.32
(3),
pp. 371-379.
show abstract
full text
BACKGROUND: Childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has been associated with early-life exposures, including birth by cesarean section (C-section), and a deficit of social exposure (first child). These exposures as proxies for microbiome acquisition in infancy are essential to prime the immune system and restrain later dysregulated immune responses that can trigger ALL in susceptible individuals. We tested risk factors pertaining to immune stimulation that may impact BCP-ALL development. METHODS: Cases comprised 1,126 children (0-12 years) with ALL (BCP-ALL: 78.5%) from the EMiLI study group in Brazil (2002-2020). Age- and sex-matched controls (n = 2,252) were randomly selected from healthy children whose mothers participated in the National Placental and Umbilical Cord Blood Bank donation. Multiple logistic regression was run fitted and adjusted for selected covariates models. RESULTS: C-section delivery was associated with increased risk for ALL [odds ratio (OR) ALL: 1.10; 95% confidence intervals (CI), 1.04-1.15; ORBCP-ALL: 1.09; 95% CI, 1.03-1.14], as well as being the firstborn child. Interaction analysis showed a significant effect of first birth on the observed C-section associations (P < 0.0001). Indeed, high-risk children, namely, firstborn children delivered via C-section were at increased risk for ALL (OR: 2.33; 95% CI, 2.40-4.84) compared with non-first, vaginally born children. An increased risk was found for firstborn children delivered by C-section and non-breastfed with ALL (ORALL: 2.32; 95% CI, 1.27-4.24; ORBCP-ALL: 2.37; 95% CI, 1.18-4.76). CONCLUSIONS: Our observations are in accord with the prediction that exposures determining microbiome composition and adrenal pathway in infancy contribute to the risk of BCP-ALL. IMPACT: These findings encourage the exploration of potential preventive interventions. See related commentary by Wiemels and Gallant, p. 292..
Peppas, I.
Ford, A.M.
Furness, C.L.
Greaves, M.F.
(2023). Gut microbiome immaturity and childhood acute lymphoblastic leukaemia. Nat rev cancer,
Vol.23
(8),
pp. 565-576.
show abstract
Acute lymphoblastic leukaemia (ALL) is the most common cancer of childhood. Here, we map emerging evidence suggesting that children with ALL at the time of diagnosis may have a delayed maturation of the gut microbiome compared with healthy children. This finding may be associated with early-life epidemiological factors previously identified as risk indicators for childhood ALL, including caesarean section birth, diminished breast feeding and paucity of social contacts. The consistently observed deficiency in short-chain fatty-acid-producing bacterial taxa in children with ALL has the potential to promote dysregulated immune responses and to, ultimately, increase the risk of transformation of preleukaemic clones in response to common infectious triggers. These data endorse the concept that a microbiome deficit in early life may contribute to the development of the major subtypes of childhood ALL and encourage the notion of risk-reducing microbiome-targeted intervention in the future..
Mansur, M.B.
deSouza, N.M.
Natrajan, R.
Abegglen, L.M.
Schiffman, J.D.
Greaves, M.
(2023). Evolutionary determinants of curability in cancer. Nat ecol evol,
Vol.7
(11),
pp. 1761-1770.
show abstract
The emergence of drug-resistant cells, most of which have a mutated TP53 gene, prevents curative treatment in most advanced and common metastatic cancers of adults. Yet, a few, rarer malignancies, all of which are TP53 wild type, have high cure rates. In this Perspective, we discuss how common features of curable cancers offer insights into the evolutionary and developmental determinants of drug resistance. Acquired loss of TP53 protein function is the most common genetic change in cancer. This probably reflects positive selection in the context of strong ecosystem pressures including microenvironmental hypoxia. Loss of TP53's functions results in multiple fitness benefits and enhanced evolvability of cancer cells. TP53-null cells survive apoptosis, and tolerate potent oncogenic signalling, DNA damage and genetic instability. In addition, critically, they provide an expanded pool of self-renewing, or stem, cells, the primary units of evolutionary selection in cancer, making subsequent adaptation to therapeutic challenge by drug resistance highly probable. The exceptional malignancies that are curable, including the common genetic subtype of childhood acute lymphoblastic leukaemia and testicular seminoma, differ from the common adult cancers in originating prenatally from embryonic or fetal cells that are developmentally primed for TP53-dependent apoptosis. Plus, they have other genetic and phenotypic features that enable dissemination without exposure to selective pressures for TP53 loss, retaining their intrinsic drug hypersensitivity..
Mansur, M.B.
Greaves, M.
(2023). Convergent TP53 loss and evolvability in cancer. Bmc ecol evol,
Vol.23
(1),
p. 54.
show abstract
full text
Cancer cell populations evolve by a stepwise process involving natural selection of the fittest variants within a tissue ecosystem context and as modified by therapy. Genomic scrutiny of patient samples reveals an extraordinary diversity of mutational profiles both between patients with similar cancers and within the cancer cell population of individual patients. Does this signify highly divergent evolutionary trajectories or are there repetitive and predictable patterns?Major evolutionary innovations or adaptations in different species are frequently repeated, or convergent, reflecting both common selective pressures and constraints on optimal solutions. We argue this is true of evolving cancer cells, especially with respect to the TP53 gene. Functional loss variants in TP53 are the most common genetic change in cancer. We discuss the likely microenvironmental selective pressures involved and the profound impact this has on cell fitness, evolvability and probability of subsequent drug resistance..
deSouza, N.M.
Choudhury, A.
Greaves, M.
O'Connor, J.P.
Hoskin, P.J.
(2022). Imaging hypoxia in endometrial cancer: How and why should it be done?. Front oncol,
Vol.12,
p. 1020907.
Greaves, M.
Cazzaniga, V.
Ford, A.
(2021). Can we prevent childhood Leukaemia?. Leukemia,
Vol.35
(5),
pp. 1258-1264.
full text
Mansur, M.B.
Furness, C.L.
Nakjang, S.
Enshaei, A.
Alpar, D.
Colman, S.M.
Minto, L.
Irving, J.
Poole, B.V.
Noronha, E.P.
Savola, S.
Iqbal, S.
Gribben, J.
Pombo-de-Oliveira, M.S.
Ford, T.M.
Greaves, M.F.
van Delft, F.W.
(2021). The genomic landscape of teenage and young adult T-cell acute lymphoblastic leukemia. Cancer med,
Vol.10
(14),
pp. 4864-4873.
show abstract
full text
BACKGROUND: Treatment on risk adapted intensive pediatric protocols has improved outcome for teenagers and young adults (TYA) with T-cell acute lymphoblastic leukemia (T-ALL). Understanding the biology of disease in this age group and the genetic basis of relapse is a key goal as patients with relapsed/refractory disease have poor outcomes with conventional chemotherapy and novel molecular targets are required. This study examines the question of whether TYA T-ALL has a specific biological-molecular profile distinct from pediatric or adult T-ALL. METHODS: Genomic characterization was undertaken of a retrospective discovery cohort of 80 patients aged 15-26 years with primary or relapsed T-ALL, using a combination of Genome-Wide Human SNP Array 6.0, targeted gene mutation and promoter methylation analyses. Findings were confirmed by MLPA, real-time quantitative PCR, and FISH. Whole Exome Sequencing was performed in 4 patients with matched presentation and relapse to model clonal evolution. A prevalence analysis was performed on a final data set of 1,792 individual cases to identify genetic lesions with age specific frequency patterns, including 972 pediatric (1-14 years), 439 TYA (15-24 years) and 381 adult (≥25 years) cases. These cases were extracted from 19 publications with comparable genomic data identified through a PubMed search. RESULTS: Genomic characterization of this large cohort of TYA T-ALL patients identified recurrent isochromosome 7q i(7q) in our discovery cohort (n = 3). Prevalence analysis did not identify any age specific genetic abnormalities. Genomic analysis of 6 pairs of matched presentation - relapsed T-ALL established that all relapses were clonally related to the initial leukemia. Whole exome sequencing analysis revealed recurrent, targetable, mutations disrupting NOTCH, PI3K/AKT/mTOR, FLT3, NRAS as well as drug metabolism pathways. CONCLUSIONS: All genetic aberrations in TYA T-ALL occurred with an incidence similar or intermediate to that reported in the pediatric and adult literature, demonstrating that overall TYA T-ALL exhibits a transitional genomic profile. Analysis of matched presentation - relapse supported the hypothesis that relapse is driven by the Darwinian evolution of sub-clones associated with drug resistance (NT5C2 and TP53 mutations) and re-iterative mutation of known key T-ALL drivers, including NOTCH1..
Turati, V.A.
Guerra-Assunção, J.A.
Potter, N.E.
Gupta, R.
Ecker, S.
Daneviciute, A.
Tarabichi, M.
Webster, A.P.
Ding, C.
May, G.
James, C.
Brown, J.
Conde, L.
Russell, L.J.
Ancliff, P.
Inglott, S.
Cazzaniga, G.
Biondi, A.
Hall, G.W.
Lynch, M.
Hubank, M.
Macaulay, I.
Beck, S.
Van Loo, P.
Jacobsen, S.E.
Greaves, M.
Herrero, J.
Enver, T.
(2021). Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia. Nat cancer,
Vol.2
(8),
pp. 835-852.
show abstract
full text
Comparison of intratumor genetic heterogeneity in cancer at diagnosis and relapse suggests that chemotherapy induces bottleneck selection of subclonal genotypes. However, evolutionary events subsequent to chemotherapy could also explain changes in clonal dominance seen at relapse. We, therefore, investigated the mechanisms of selection in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) during induction chemotherapy where maximal cytoreduction occurs. To distinguish stochastic versus deterministic events, individual leukemias were transplanted into multiple xenografts and chemotherapy administered. Analyses of the immediate post-treatment leukemic residuum at single-cell resolution revealed that chemotherapy has little impact on genetic heterogeneity. Rather, it acts on extensive, previously unappreciated, transcriptional and epigenetic heterogeneity in BCP-ALL, dramatically reducing the spectrum of cell states represented, leaving a genetically polyclonal but phenotypically uniform population with hallmark signatures relating to developmental stage, cell cycle and metabolism. Hence, canalization of cell state accounts for a significant component of bottleneck selection during induction chemotherapy..
Ermini, L.
Francis, J.C.
Rosa, G.S.
Rose, A.J.
Ning, J.
Greaves, M.
Swain, A.
(2021). Evolutionary selection of alleles in the melanophilin gene that impacts on prostate organ function and cancer risk. Evol med public health,
Vol.9
(1),
pp. 311-321.
show abstract
full text
BACKGROUND AND OBJECTIVES: Several hundred inherited genetic variants or SNPs that alter the risk of cancer have been identified through genome-wide association studies. In populations of European ancestry, these variants are mostly present at relatively high frequencies. To gain insight into evolutionary origins, we screened a series of genes and SNPs linked to breast or prostate cancer for signatures of historical positive selection. METHODOLOGY: We took advantage of the availability of the 1000 genome data and we performed genomic scans for positive selection in five different Caucasian populations as well as one African reference population. We then used prostate organoid cultures to provide a possible functional explanation for the interplay between the action of evolutionary forces and the disease risk association. RESULTS: Variants in only one gene showed genomic signatures of positive, evolutionary selection within Caucasian populations melanophilin (MLPH). Functional depletion of MLPH in prostate organoids, by CRISPR/Cas9 mutation, impacted lineage commitment of progenitor cells promoting luminal versus basal cell differentiation and on resistance to androgen deprivation. CONCLUSIONS AND IMPLICATIONS: The MLPH variants influencing prostate cancer risk may have been historically selected for their adaptive benefit on skin pigmentation but MLPH is highly expressed in the prostate and the derivative, positively selected, alleles decrease the risk of prostate cancer. Our study suggests a potential functional mechanism via which MLPH and its genetic variants could influence risk of prostate cancer, as a serendipitous consequence of prior evolutionary benefits to another tissue. LAY SUMMARY: We screened a limited series of genomic variants associated with breast and prostate cancer risk for signatures of historical positive selection. Variants within the melanophilin (MLPH) gene fell into this category. Depletion of MLPH in prostate organoid cultures, suggested a potential functional mechanism for impacting on cancer risk, as a serendipitous consequence of prior evolutionary benefits to another tissue..
Greaves, M.
(2020). COVID-19 and childhood acute lymphoblastic leukemia. Pediatr blood cancer,
Vol.67
(12),
p. e28481.
Potter, N.
Miraki-Moud, F.
Ermini, L.
Titley, I.
Vijayaraghavan, G.
Papaemmanuil, E.
Campbell, P.
Gribben, J.
Taussig, D.
Greaves, M.
(2019). Single cell analysis of clonal architecture in acute myeloid leukaemia. Leukemia,
Vol.33
(5),
pp. 1113-1123.
show abstract
full text
We used single cell Q-PCR on a micro-fluidic platform (Fluidigm) to analyse clonal, genetic architecture and phylogeny in acute myeloid leukaemia (AML) using selected mutations. Ten cases of NPM1c mutant AML were screened for 111 mutations that are recurrent in AML and cancer. Clonal architectures were relatively simple with one to six sub-clones and were branching in some, but not all, patients. NPM1 mutations were secondary or sub-clonal to other driver mutations (DNM3TA, TET2, WT1 and IDH2) in all cases. In three of the ten cases, single cell analysis of enriched CD34+/CD33- cells revealed a putative pre-leukaemic sub-clone, undetectable in the bulk CD33+ population that had one or more driver mutations but lacked NPM1c. Cells from all cases were transplanted into NSG mice and in most (8/10), more than one sub-clone (#2-5 sub-clones) transplanted. However, the dominant regenerating sub-clone in 9/10 cases was NPM1+ and this sub-clone was either dominant or minor in the diagnostic sample from which it was derived. This study provides further evidence, at the single cell level, for genetic variegation in sub-clones and stem cells in acute leukaemia and demonstrates both a preferential order of mutation accrual and parallel evolution of sub-clones..
Jones, J.R.
Weinhold, N.
Ashby, C.
Walker, B.A.
Wardell, C.
Pawlyn, C.
Rasche, L.
Melchor, L.
Cairns, D.A.
Gregory, W.M.
Johnson, D.
Begum, D.B.
Ellis, S.
Sherborne, A.L.
Cook, G.
Kaiser, M.F.
Drayson, M.T.
Owen, R.G.
Jackson, G.H.
Davies, F.E.
Greaves, M.
Morgan, G.J.
NCRI Haemato-Oncology CSG,
(2019). Clonal evolution in myeloma: the impact of maintenance lenalidomide and depth of response on the genetics and sub-clonal structure of relapsed disease in uniformly treated newly diagnosed patients. Haematologica,
Vol.104
(7),
pp. 1440-1450.
show abstract
full text
The emergence of treatment resistant sub-clones is a key feature of relapse in multiple myeloma. Therapeutic attempts to extend remission and prevent relapse include maximizing response and the use of maintenance therapy. We used whole exome sequencing to study the genetics of paired samples taken at presentation and at relapse from 56 newly diagnosed patients, following induction therapy, randomized to receive either lenalidomide maintenance or observation as part of the Myeloma XI trial. Patients included were considered high risk, relapsing within 30 months of maintenance randomization. Patients achieving a complete response had predominantly branching evolutionary patterns leading to relapse, characterized by a greater mutational burden, an altered mutational profile, bi-allelic inactivation of tumor suppressor genes, and acquired structural aberrations. Conversely, in patients achieving a partial response, the evolutionary features were predominantly stable with a similar mutational and structural profile seen at both time points. There were no significant differences between patients relapsing after lenalidomide maintenance versus observation. This study shows that the depth of response is a key determinant of the evolutionary patterns seen at relapse. This trial is registered at clinicaltrials.gov identifier: 01554852..
Greaves, M.
(2018). A causal mechanism for childhood acute lymphoblastic leukaemia. Nat rev cancer,
Vol.18
(8),
pp. 471-484.
show abstract
full text
In this Review, I present evidence supporting a multifactorial causation of childhood acute lymphoblastic leukaemia (ALL), a major subtype of paediatric cancer. ALL evolves in two discrete steps. First, in utero initiation by fusion gene formation or hyperdiploidy generates a covert, pre-leukaemic clone. Second, in a small fraction of these cases, the postnatal acquisition of secondary genetic changes (primarily V(D)J recombination-activating protein (RAG) and activation-induced cytidine deaminase (AID)-driven copy number alterations in the case of ETS translocation variant 6 (ETV6)-runt-related transcription factor 1 (RUNX1)+ ALL) drives conversion to overt leukaemia. Epidemiological and modelling studies endorse a dual role for common infections. Microbial exposures earlier in life are protective but, in their absence, later infections trigger the critical secondary mutations. Risk is further modified by inherited genetics, chance and, probably, diet. Childhood ALL can be viewed as a paradoxical consequence of progress in modern societies, where behavioural changes have restrained early microbial exposure. This engenders an evolutionary mismatch between historical adaptations of the immune system and contemporary lifestyles. Childhood ALL may be a preventable cancer..
Furness, C.L.
Mansur, M.B.
Weston, V.J.
Ermini, L.
van Delft, F.W.
Jenkinson, S.
Gale, R.
Harrison, C.J.
Pombo-de-Oliveira, M.S.
Sanchez-Martin, M.
Ferrando, A.A.
Kearns, P.
Titley, I.
Ford, A.M.
Potter, N.E.
Greaves, M.
(2018). The subclonal complexity of STIL-TAL1+ T-cell acute lymphoblastic leukaemia. Leukemia,
Vol.32
(9),
pp. 1984-1993.
show abstract
full text
Single-cell genetics were used to interrogate clonal complexity and the sequence of mutational events in STIL-TAL1+ T-ALL. Single-cell multicolour FISH was used to demonstrate that the earliest detectable leukaemia subclone contained the STIL-TAL1 fusion and copy number loss of 9p21.3 (CDKN2A/CDKN2B locus), with other copy number alterations including loss of PTEN occurring as secondary subclonal events. In three cases, multiplex qPCR and phylogenetic analysis were used to produce branching evolutionary trees recapitulating the snapshot history of T-ALL evolution in this leukaemia subtype, which confirmed that mutations in key T-ALL drivers, including NOTCH1 and PTEN, were subclonal and reiterative in distinct subclones. Xenografting confirmed that self-renewing or propagating cells were genetically diverse. These data suggest that the STIL-TAL1 fusion is a likely founder or truncal event. Therapies targeting the TAL1 auto-regulatory complex are worthy of further investigation in T-ALL..
Vijayakrishnan, J.
Studd, J.
Broderick, P.
Kinnersley, B.
Holroyd, A.
Law, P.J.
Kumar, R.
Allan, J.M.
Harrison, C.J.
Moorman, A.V.
Vora, A.
Roman, E.
Rachakonda, S.
Kinsey, S.E.
Sheridan, E.
Thompson, P.D.
Irving, J.A.
Koehler, R.
Hoffmann, P.
Nöthen, M.M.
Heilmann-Heimbach, S.
Jöckel, K.-.
Easton, D.F.
Pharaoh, P.D.
Dunning, A.M.
Peto, J.
Canzian, F.
Swerdlow, A.
Eeles, R.A.
Kote-Jarai, Z.
Muir, K.
Pashayan, N.
PRACTICAL Consortium,
Greaves, M.
Zimmerman, M.
Bartram, C.R.
Schrappe, M.
Stanulla, M.
Hemminki, K.
Houlston, R.S.
(2018). Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia. Nat commun,
Vol.9
(1),
p. 1340.
show abstract
full text
Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P = 3.86 × 10-9, odds ratio (OR) = 1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, P = 3.20 × 10-8, OR = 2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology..
Greaves, M.
(2018). Nothing in cancer makes sense except…. Bmc biol,
Vol.16
(1),
p. 22.
show abstract
full text
Paraphrasing Dobzhansky's famous dictum, I discuss how interrogating cancer through the lens of evolution has transformed our understanding of its development, causality and treatment resistance. The emerging picture of cancer captures its extensive diversity and therapeutic resilience, highlighting the need for more innovative approaches to control..
Greaves, M.
Hughes, W.
(2018). Cancer cell transmission via the placenta. Evol med public health,
Vol.2018
(1),
pp. 106-115.
show abstract
full text
Cancer cells have a parasitic propensity in the primary host but their capacity to transit between individuals is severely restrained by two factors: a lack of a route for viable cell transfer and immune recognition in allogeneic, secondary recipients. Several examples of transmissible animal cancers are now recognised. In humans, the only natural route for transmission is via the haemochorial placenta which is permissive for cell traffic. There are three special examples of this occurring in utero: maternal to foetus, intraplacental twin to twin leukaemias and choriocarcinoma-extra-embryonic cells to mother. We discuss the rare circumstances under which such transmission occurs..
Lote, H.
Spiteri, I.
Ermini, L.
Vatsiou, A.
Roy, A.
McDonald, A.
Maka, N.
Balsitis, M.
Bose, N.
Simbolo, M.
Mafficini, A.
Lampis, A.
Hahne, J.C.
Trevisani, F.
Eltahir, Z.
Mentrasti, G.
Findlay, C.
Kalkman, E.A.
Punta, M.
Werner, B.
Lise, S.
Aktipis, A.
Maley, C.
Greaves, M.
Braconi, C.
White, J.
Fassan, M.
Scarpa, A.
Sottoriva, A.
Valeri, N.
(2017). Carbon dating cancer: defining the chronology of metastatic progression in colorectal cancer. Ann oncol,
Vol.28
(6),
pp. 1243-1249.
show abstract
full text
BACKGROUND: Patients often ask oncologists how long a cancer has been present before causing symptoms or spreading to other organs. The evolutionary trajectory of cancers can be defined using phylogenetic approaches but lack of chronological references makes dating the exact onset of tumours very challenging. PATIENTS AND METHODS: Here, we describe the case of a colorectal cancer (CRC) patient presenting with synchronous lung metastasis and metachronous thyroid, chest wall and urinary tract metastases over the course of 5 years. The chest wall metastasis was caused by needle tract seeding, implying a known time of onset. Using whole genome sequencing data from primary and metastatic sites we inferred the complete chronology of the cancer by exploiting the time of needle tract seeding as an in vivo 'stopwatch'. This approach allowed us to follow the progression of the disease back in time, dating each ancestral node of the phylogenetic tree in the past history of the tumour. We used a Bayesian phylogenomic approach, which accounts for possible dynamic changes in mutational rate, to reconstruct the phylogenetic tree and effectively 'carbon date' the malignant progression. RESULTS: The primary colon cancer emerged between 5 and 8 years before the clinical diagnosis. The primary tumour metastasized to the lung and the thyroid within a year from its onset. The thyroid lesion presented as a tumour-to-tumour deposit within a benign Hurthle adenoma. Despite rapid metastatic progression from the primary tumour, the patient showed an indolent disease course. Primary cancer and metastases were microsatellite stable and displayed low chromosomal instability. Neo-antigen analysis suggested minimal immunogenicity. CONCLUSION: Our data provide the first in vivo experimental evidence documenting the timing of metastatic progression in CRC and suggest that genomic instability might be more important than the metastatic potential of the primary cancer in dictating CRC fate..
Vijayakrishnan, J.
Kumar, R.
Henrion, M.Y.
Moorman, A.V.
Rachakonda, P.S.
Hosen, I.
da Silva Filho, M.I.
Holroyd, A.
Dobbins, S.E.
Koehler, R.
Thomsen, H.
Irving, J.A.
Allan, J.M.
Lightfoot, T.
Roman, E.
Kinsey, S.E.
Sheridan, E.
Thompson, P.D.
Hoffmann, P.
Nöthen, M.M.
Heilmann-Heimbach, S.
Jöckel, K.H.
Greaves, M.
Harrison, C.J.
Bartram, C.R.
Schrappe, M.
Stanulla, M.
Hemminki, K.
Houlston, R.S.
(2017). A genome-wide association study identifies risk loci for childhood acute lymphoblastic leukemia at 10q26 13 and 12q23 1. Leukemia,
Vol.31
(3),
pp. 573-579.
show abstract
full text
Genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of childhood acute lymphoblastic leukemia (ALL). To identify new susceptibility loci for the largest subtype of ALL, B-cell precursor ALL (BCP-ALL), we conducted a meta-analysis of two GWASs with imputation using 1000 Genomes and UK10K Project data as reference (totaling 1658 cases and 7224 controls). After genotyping an additional 2525 cases and 3575 controls, we identify new susceptibility loci for BCP-ALL mapping to 10q26.13 (rs35837782, LHPP, P=1.38 × 10-11) and 12q23.1 (rs4762284, ELK3, P=8.41 × 10-9). We also provide confirmatory evidence for the existence of independent risk loci at 9p21.3, but show that the association marked by rs77728904 can be accounted for by linkage disequilibrium with the rare high-impact CDKN2A p.Ala148Thr variant rs3731249. Our data provide further insights into genetic susceptibility to ALL and its biology..
Cazzaniga, G.
Bisanti, L.
Randi, G.
Deandrea, S.
Bungaro, S.
Pregliasco, F.
Perotti, D.
Spreafico, F.
Masera, G.
Valsecchi, M.G.
Biondi, A.
Greaves, M.
(2017). Possible role of pandemic AH1N1 swine flu virus in a childhood leukemia cluster. Leukemia,
Vol.31
(8),
pp. 1819-1821.
full text
Maley, C.C.
Aktipis, A.
Graham, T.A.
Sottoriva, A.
Boddy, A.M.
Janiszewska, M.
Silva, A.S.
Gerlinger, M.
Yuan, Y.
Pienta, K.J.
Anderson, K.S.
Gatenby, R.
Swanton, C.
Posada, D.
Wu, C.-.
Schiffman, J.D.
Hwang, E.S.
Polyak, K.
Anderson, A.R.
Brown, J.S.
Greaves, M.
Shibata, D.
(2017). Classifying the evolutionary and ecological features of neoplasms. Nat rev cancer,
Vol.17
(10),
pp. 605-619.
show abstract
full text
Neoplasms change over time through a process of cell-level evolution, driven by genetic and epigenetic alterations. However, the ecology of the microenvironment of a neoplastic cell determines which changes provide adaptive benefits. There is widespread recognition of the importance of these evolutionary and ecological processes in cancer, but to date, no system has been proposed for drawing clinically relevant distinctions between how different tumours are evolving. On the basis of a consensus conference of experts in the fields of cancer evolution and cancer ecology, we propose a framework for classifying tumours that is based on four relevant components. These are the diversity of neoplastic cells (intratumoural heterogeneity) and changes over time in that diversity, which make up an evolutionary index (Evo-index), as well as the hazards to neoplastic cell survival and the resources available to neoplastic cells, which make up an ecological index (Eco-index). We review evidence demonstrating the importance of each of these factors and describe multiple methods that can be used to measure them. Development of this classification system holds promise for enabling clinicians to personalize optimal interventions based on the evolvability of the patient's tumour. The Evo- and Eco-indices provide a common lexicon for communicating about how neoplasms change in response to interventions, with potential implications for clinical trials, personalized medicine and basic cancer research..
Greaves, M.
(2016). Leukaemia 'firsts' in cancer research and treatment. Nat rev cancer,
Vol.16
(3),
pp. 163-172.
show abstract
Our understanding of cancer biology has been radically transformed over recent years with a more realistic grasp of its multilayered cellular and genetic complexity. These advances are being translated into more selective and effective treatment of cancers and, although there are still considerable challenges, particularly with drug resistance and metastatic disease, many patients with otherwise lethal malignancies now enjoy protracted remissions or cure. One largely unheralded theme of this story is the extent to which new biological insights and novel clinical applications have their origins with leukaemia and related blood cell cancers, including lymphoma. In this Timeline article, I review the remarkable and ground-breaking role that studies in leukaemia have had at the forefront of this progress..
Papaemmanuil, E.
Gerstung, M.
Bullinger, L.
Gaidzik, V.I.
Paschka, P.
Roberts, N.D.
Potter, N.E.
Heuser, M.
Thol, F.
Bolli, N.
Gundem, G.
Van Loo, P.
Martincorena, I.
Ganly, P.
Mudie, L.
McLaren, S.
O'Meara, S.
Raine, K.
Jones, D.R.
Teague, J.W.
Butler, A.P.
Greaves, M.F.
Ganser, A.
Döhner, K.
Schlenk, R.F.
Döhner, H.
Campbell, P.J.
(2016). Genomic Classification and Prognosis in Acute Myeloid Leukemia. N engl j med,
Vol.374
(23),
pp. 2209-2221.
show abstract
full text
BACKGROUND: Recent studies have provided a detailed census of genes that are mutated in acute myeloid leukemia (AML). Our next challenge is to understand how this genetic diversity defines the pathophysiology of AML and informs clinical practice. METHODS: We enrolled a total of 1540 patients in three prospective trials of intensive therapy. Combining driver mutations in 111 cancer genes with cytogenetic and clinical data, we defined AML genomic subgroups and their relevance to clinical outcomes. RESULTS: We identified 5234 driver mutations across 76 genes or genomic regions, with 2 or more drivers identified in 86% of the patients. Patterns of co-mutation compartmentalized the cohort into 11 classes, each with distinct diagnostic features and clinical outcomes. In addition to currently defined AML subgroups, three heterogeneous genomic categories emerged: AML with mutations in genes encoding chromatin, RNA-splicing regulators, or both (in 18% of patients); AML with TP53 mutations, chromosomal aneuploidies, or both (in 13%); and, provisionally, AML with IDH2(R172) mutations (in 1%). Patients with chromatin-spliceosome and TP53-aneuploidy AML had poor outcomes, with the various class-defining mutations contributing independently and additively to the outcome. In addition to class-defining lesions, other co-occurring driver mutations also had a substantial effect on overall survival. The prognostic effects of individual mutations were often significantly altered by the presence or absence of other driver mutations. Such gene-gene interactions were especially pronounced for NPM1-mutated AML, in which patterns of co-mutation identified groups with a favorable or adverse prognosis. These predictions require validation in prospective clinical trials. CONCLUSIONS: The driver landscape in AML reveals distinct molecular subgroups that reflect discrete paths in the evolution of AML, informing disease classification and prognostic stratification. (Funded by the Wellcome Trust and others; ClinicalTrials.gov number, NCT00146120.)..
Bateman, C.M.
Alpar, D.
Ford, A.M.
Colman, S.M.
Wren, D.
Morgan, M.
Kearney, L.
Greaves, M.
(2015). Evolutionary trajectories of hyperdiploid ALL in monozygotic twins. Leukemia,
Vol.29
(1),
pp. 58-65.
show abstract
Identical twins have provided unique insights on timing or sequence of genetic events in acute lymphoblastic leukaemia (ALL). To date, this has mainly focused on ALL with MLL or ETV6-RUNX1 fusions, with hyperdiploid ALL remaining less well characterised. We examined three pairs of monozygotic twins, two concordant and one discordant for hyperdiploid ALL, for single-nucleotide polymorphism (SNP)-defined copy number alterations (CNAs), IGH/L plus TCR gene rearrangements and mutations in NRAS, KRAS, FLT3 and PTPN11 genes. We performed whole exome sequencing in one concordant twin pair. Potential 'driver' CNAs were low, 0-3 per case, and all were different within a pair. One patient had an NRAS mutation that was lacking from leukaemic cells of the twin sibling. By exome sequencing, there were 12 nonsynonymous mutations found in one twin and 5 in the other, one of which in SCL44A2 was shared or identical. Concordant pairs had some identical IGH/L and TCR rearrangements. In the twin pair with discordant hyperdiploid ALL, the healthy co-twin had persistent low level hyperdiploid CD19+ cells that lacked a CNA present in the ALL cells of her sibling. From these data, we propose that hyperdiploid ALL arises in a pre-B cell in utero and mutational changes necessary for clinical ALL accumulate subclonally and postnatally..
Greaves, M.
Ermini, L.
(2015). Evolutionary Adaptations to Risk of Cancer: Evidence From Cancer Resistance in Elephants. Jama,
Vol.314
(17),
pp. 1806-1807.
Alpar, D.
Wren, D.
Ermini, L.
Mansur, M.B.
van Delft, F.W.
Bateman, C.M.
Titley, I.
Kearney, L.
Szczepanski, T.
Gonzalez, D.
Ford, A.M.
Potter, N.E.
Greaves, M.
(2015). Clonal origins of ETV6-RUNX1⁺ acute lymphoblastic leukemia: studies in monozygotic twins. Leukemia,
Vol.29
(4),
pp. 839-846.
show abstract
Studies on twins with concordant acute lymphoblastic leukemia (ALL) have revealed that ETV6-RUNX1 gene fusion is a common, prenatal genetic event with other driver aberrations occurring subclonally and probably postnatally. The fetal cell type that is transformed by ETV6-RUNX1 is not identified by such studies or by the analysis of early B-cell lineage phenotype of derived progeny. Ongoing, clonal immunoglobulin (IG) and cross-lineage T-cell receptor (TCR) gene rearrangements are features of B-cell precursor leukemia and commence at the pro-B-cell stage of normal B-cell lineage development. We reasoned that shared clonal rearrangements of IG or TCR genes by concordant ALL in twins would be informative about the fetal cell type in which clonal advantage is elicited by ETV6-RUNX1. Five pairs of twins were analyzed for all varieties of IG and TCR gene rearrangements. All pairs showed identical incomplete or complete variable-diversity-joining junctions coupled with substantial, subclonal and divergent rearrangements. This pattern was endorsed by single-cell genetic scrutiny in one twin pair. Our data suggest that the pre-leukemic initiating function of ETV6-RUNX1 fusion is associated with clonal expansion early in the fetal B-cell lineage..
Swaminathan, S.
Klemm, L.
Park, E.
Papaemmanuil, E.
Ford, A.
Kweon, S.-.
Trageser, D.
Hasselfeld, B.
Henke, N.
Mooster, J.
Geng, H.
Schwarz, K.
Kogan, S.C.
Casellas, R.
Schatz, D.G.
Lieber, M.R.
Greaves, M.F.
Müschen, M.
(2015). Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia. Nat immunol,
Vol.16
(7),
pp. 766-774.
show abstract
Childhood acute lymphoblastic leukemia (ALL) can often be traced to a pre-leukemic clone carrying a prenatal genetic lesion. Postnatally acquired mutations then drive clonal evolution toward overt leukemia. The enzymes RAG1-RAG2 and AID, which diversify immunoglobulin-encoding genes, are strictly segregated in developing cells during B lymphopoiesis and peripheral mature B cells, respectively. Here we identified small pre-BII cells as a natural subset with increased genetic vulnerability owing to concurrent activation of these enzymes. Consistent with epidemiological findings on childhood ALL etiology, susceptibility to genetic lesions during B lymphopoiesis at the transition from the large pre-BII cell stage to the small pre-BII cell stage was exacerbated by abnormal cytokine signaling and repetitive inflammatory stimuli. We demonstrated that AID and RAG1-RAG2 drove leukemic clonal evolution with repeated exposure to inflammatory stimuli, paralleling chronic infections in childhood..
Greaves, M.
(2015). Evolutionary determinants of cancer. Cancer discov,
Vol.5
(8),
pp. 806-820.
show abstract
UNLABELLED: Our understanding of cancer is being transformed by exploring clonal diversity, drug resistance, and causation within an evolutionary framework. The therapeutic resilience of advanced cancer is a consequence of its character as a complex, dynamic, and adaptive ecosystem engendering robustness, underpinned by genetic diversity and epigenetic plasticity. The risk of mutation-driven escape by self-renewing cells is intrinsic to multicellularity but is countered by multiple restraints, facilitating increasing complexity and longevity of species. But our own species has disrupted this historical narrative by rapidly escalating intrinsic risk. Evolutionary principles illuminate these challenges and provide new avenues to explore for more effective control. SIGNIFICANCE: Lifetime risk of cancer now approximates to 50% in Western societies. And, despite many advances, the outcome for patients with disseminated disease remains poor, with drug resistance the norm. An evolutionary perspective may provide a clearer understanding of how cancer clones develop robustness and why, for us as a species, risk is now off the scale. And, perhaps, of what we might best do to achieve more effective control..
Ford, A.M.
Mansur, M.B.
Furness, C.L.
van Delft, F.W.
Okamura, J.
Suzuki, T.
Kobayashi, H.
Kaneko, Y.
Greaves, M.
(2015). Protracted dormancy of pre-leukemic stem cells. Leukemia,
Vol.29
(11),
pp. 2202-2207.
show abstract
full text
Cancer stem cells can escape therapeutic killing by adopting a quiescent or dormant state. The reversibility of this condition provides the potential for later recurrence or relapse, potentially many years later. We describe the genomics of a rare case of childhood BCR-ABL1-positive, B-cell precursor acute lymphoblastic leukemia that relapsed, with an acute myeloblastic leukemia immunophenotype, 22 years after the initial diagnosis, sustained remission and presumed cure. The primary and relapsed leukemias shared the identical BCR-ABL1 fusion genomic sequence and two identical immunoglobulin gene rearrangements, indicating that the relapse was a derivative of the founding clone. All other mutational changes (single-nucleotide variant and copy number alterations) were distinct in diagnostic or relapse samples. These data provide unambiguous evidence that leukemia-propagating cells, most probably pre-leukemic stem cells, can remain covert and silent but potentially reactivatable for more than two decades..
Mansur, M.B.
van Delft, F.W.
Colman, S.M.
Furness, C.L.
Gibson, J.
Emerenciano, M.
Kempski, H.
Clappier, E.
Cave, H.
Soulier, J.
Pombo-de-Oliveira, M.S.
Greaves, M.
Ford, A.M.
(2015). Distinctive genotypes in infants with T-cell acute lymphoblastic leukaemia. Br j haematol,
Vol.171
(4),
pp. 574-584.
show abstract
Infant T-cell acute lymphoblastic leukaemia (iT-ALL) is a very rare and poorly defined entity with a poor prognosis. We assembled a unique series of 13 infants with T-ALL, which allowed us to identify genotypic abnormalities and to investigate prenatal origins. Matched samples (diagnosis/remission) were analysed by single nucleotide polymorphism-array to identify genomic losses and gains. In three cases, we identified a recurrent somatic deletion on chromosome 3. These losses result in the complete deletion of MLF1 and have not previously been described in T-ALL. We observed two cases with an 11p13 deletion (LMO2-related), one of which also harboured a deletion of RB1. Another case presented a large 11q14·1-11q23·2 deletion that included ATM and only five patients (38%) showed deletions of CDKN2A/B. Four cases showed NOTCH1 mutations; in one case FBXW7 was the sole mutation and three cases showed alterations in PTEN. KMT2A rearrangements (KMT2A-r) were detected in three out of 13 cases. For three patients, mutations and copy number alterations (including deletion of PTEN) could be backtracked to birth using neonatal blood spot DNA, demonstrating an in utero origin. Overall, our data indicates that iT-ALL has a diverse but distinctive profile of genotypic abnormalities when compared to T-ALL in older children and adults..
Greaves, M.
Müschen, M.
(2015). Infection and the Perils of B-cell Activation. Cancer discov,
Vol.5
(12),
pp. 1244-1246.
show abstract
Recent studies have linked aberrant B-cell activation in the context of aberrant immune responses to infectious pathogens to malignant transformation and development of leukemia and lymphoma. A new study in this issue demonstrates that common infections can be drivers of clonal evolution of premalignant B-cell precursors toward childhood leukemia..
Greaves, M.
(2015). When one mutation is all it takes. Cancer cell,
Vol.27
(4),
pp. 433-434.
show abstract
In a recent issue of Nature Genetics, Andersson and colleagues report that MLL fusion alone may be sufficient to spawn an aggressive leukemia in infants. Some other pediatric cancers may share a similar, single, "big-hit" origin, possibly reflecting a critical developmental window of stem cell vulnerability..
Piccirillo, S.G.
Colman, S.
Potter, N.E.
van Delft, F.W.
Lillis, S.
Carnicer, M.-.
Kearney, L.
Watts, C.
Greaves, M.
(2015). Genetic and functional diversity of propagating cells in glioblastoma. Stem cell reports,
Vol.4
(1),
pp. 7-15.
show abstract
full text
Glioblastoma (GBM) is a lethal malignancy whose clinical intransigence has been linked to extensive intraclonal genetic and phenotypic diversity and the common emergence of therapeutic resistance. This interpretation embodies the implicit assumption that cancer stem cells or tumor-propagating cells are themselves genetically and functionally diverse. To test this, we screened primary GBM tumors by SNP array to identify copy number alterations (a minimum of three) that could be visualized in single cells by multicolor fluorescence in situ hybridization. Interrogation of neurosphere-derived cells (from four patients) and cells derived from secondary transplants of these same cells in NOD-SCID mice allowed us to infer the clonal and phylogenetic architectures. Whole-exome sequencing and single-cell genetic analysis in one case revealed a more complex clonal structure. This proof-of-principle experiment revealed that subclones in each GBM had variable regenerative or stem cell activity, and highlighted genetic alterations associated with more competitive propagating activity in vivo..
Vijayakrishnan, J.
Henrion, M.
Moorman, A.V.
Fiege, B.
Kumar, R.
da Silva Filho, M.I.
Holroyd, A.
Koehler, R.
Thomsen, H.
Irving, J.A.
Allan, J.M.
Lightfoot, T.
Roman, E.
Kinsey, S.E.
Sheridan, E.
Thompson, P.D.
Hoffmann, P.
Nöthen, M.M.
Mühleisen, T.W.
Eisele, L.
Bartram, C.R.
Schrappe, M.
Greaves, M.
Hemminki, K.
Harrison, C.J.
Stanulla, M.
Houlston, R.S.
(2015). The 9p21 3 risk of childhood acute lymphoblastic leukaemia is explained by a rare high-impact variant in CDKN2A. Sci rep,
Vol.5,
p. 15065.
show abstract
Genome-wide association studies (GWAS) have provided strong evidence for inherited predisposition to childhood acute lymphoblastic leukaemia (ALL) identifying a number of risk loci. We have previously shown common SNPs at 9p21.3 influence ALL risk. These SNP associations are generally not themselves candidates for causality, but simply act as markers for functional variants. By means of imputation of GWAS data and subsequent validation SNP genotyping totalling 2,177 ALL cases and 8,240 controls, we have shown that the 9p21.3 association can be ascribed to the rare high-impact CDKN2A p.Ala148Thr variant (rs3731249; Odds ratio = 2.42, P = 3.45 × 10(-19)). The association between rs3731249 genotype and risk was not specific to particular subtype of B-cell ALL. The rs3731249 variant is associated with predominant nuclear localisation of the CDKN2A transcript suggesting the functional effect of p.Ala148Thr on ALL risk may be through compromised ability to inhibit cyclin D within the cytoplasm..
Greaves, M.
(2015). Cancer's Darwinian dilemma: an evolutionary tale in three acts. Bmj,
Vol.351,
p. h6581.
Ju, Y.S.
Alexandrov, L.B.
Gerstung, M.
Martincorena, I.
Nik-Zainal, S.
Ramakrishna, M.
Davies, H.R.
Papaemmanuil, E.
Gundem, G.
Shlien, A.
Bolli, N.
Behjati, S.
Tarpey, P.S.
Nangalia, J.
Massie, C.E.
Butler, A.P.
Teague, J.W.
Vassiliou, G.S.
Green, A.R.
Du, M.-.
Unnikrishnan, A.
Pimanda, J.E.
Teh, B.T.
Munshi, N.
Greaves, M.
Vyas, P.
El-Naggar, A.K.
Santarius, T.
Collins, V.P.
Grundy, R.
Taylor, J.A.
Hayes, D.N.
Malkin, D.
ICGC Breast Cancer Group,
ICGC Chronic Myeloid Disorders Group,
ICGC Prostate Cancer Group,
Foster, C.S.
Warren, A.Y.
Whitaker, H.C.
Brewer, D.
Eeles, R.
Cooper, C.
Neal, D.
Visakorpi, T.
Isaacs, W.B.
Bova, G.S.
Flanagan, A.M.
Futreal, P.A.
Lynch, A.G.
Chinnery, P.F.
McDermott, U.
Stratton, M.R.
Campbell, P.J.
(2014). Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer. Elife,
Vol.3.
show abstract
full text
Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. In this study, we analyzed somatic alterations in mtDNA from 1675 tumors. We identified 1907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C > T and A > G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. A number of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria and is fundamentally linked to mtDNA replication..
Papaemmanuil, E.
Rapado, I.
Li, Y.
Potter, N.E.
Wedge, D.C.
Tubio, J.
Alexandrov, L.B.
Van Loo, P.
Cooke, S.L.
Marshall, J.
Martincorena, I.
Hinton, J.
Gundem, G.
van Delft, F.W.
Nik-Zainal, S.
Jones, D.R.
Ramakrishna, M.
Titley, I.
Stebbings, L.
Leroy, C.
Menzies, A.
Gamble, J.
Robinson, B.
Mudie, L.
Raine, K.
O'Meara, S.
Teague, J.W.
Butler, A.P.
Cazzaniga, G.
Biondi, A.
Zuna, J.
Kempski, H.
Muschen, M.
Ford, A.M.
Stratton, M.R.
Greaves, M.
Campbell, P.J.
(2014). RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia. Nat genet,
Vol.46
(2),
pp. 116-125.
show abstract
The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL) cases, is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, characterized by recombination signal sequence motifs near breakpoints, incorporation of non-templated sequence at junctions, ∼30-fold enrichment at promoters and enhancers of genes actively transcribed in B cell development and an unexpectedly high ratio of recurrent to non-recurrent structural variants. Single-cell tracking shows that this mechanism is active throughout leukemic evolution, with evidence of localized clustering and reiterated deletions. Integration of data on point mutations and rearrangements identifies ATF7IP and MGA as two new tumor-suppressor genes in ALL. Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1-positive lymphoblasts, targeting the promoters, enhancers and first exons of genes that normally regulate B cell differentiation..
Greaves, M.
(2014). Does everyone develop covert cancer?. Nature reviews cancer,
Vol.14
(4),
pp. 209-210.
Greaves, M.
(2014). Retrospective Janet Rowley (1925-2013). Science,
Vol.343
(6171),
p. 626.
Cooke, S.L.
Shlien, A.
Marshall, J.
Pipinikas, C.P.
Martincorena, I.
Tubio, J.M.
Li, Y.
Menzies, A.
Mudie, L.
Ramakrishna, M.
Yates, L.
Davies, H.
Bolli, N.
Bignell, G.R.
Tarpey, P.S.
Behjati, S.
Nik-Zainal, S.
Papaemmanuil, E.
Teixeira, V.H.
Raine, K.
O'Meara, S.
Dodoran, M.S.
Teague, J.W.
Butler, A.P.
Iacobuzio-Donahue, C.
Santarius, T.
Grundy, R.G.
Malkin, D.
Greaves, M.
Munshi, N.
Flanagan, A.M.
Bowtell, D.
Martin, S.
Larsimont, D.
Reis-Filho, J.S.
Boussioutas, A.
Taylor, J.A.
Hayes, N.D.
Janes, S.M.
Futreal, P.A.
Stratton, M.R.
McDermott, U.
Campbell, P.J.
ICGC Breast Cancer Group,
(2014). Processed pseudogenes acquired somatically during cancer development. Nat commun,
Vol.5,
p. 3644.
show abstract
Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5' truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA, abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially diverse functional consequences depending on genomic context..
Watts, C.
Piccirillo, S.
Kearney, L.
Potter, N.
van Delft, F.
Coleman, S.
Lillis, S.
Carnicer, M.-.
Greaves, M.
(2014). INTERROGATION OF SUB-CLONAL GENETIC DIVERSITY OF HUMAN GBM REVEALS GENETIC HETEROGENEITY IN TUMOUR-PROPAGATING CELLS, WHICH DISPLAY VARIABLE COMPETITIVE CAPACITY FOR TUMOUR PROPAGATION IN VIVO. Neuro-oncology,
Vol.16.
Palmi, C.
Fazio, G.
Savino, A.M.
Procter, J.
Howell, L.
Cazzaniga, V.
Vieri, M.
Longinotti, G.
Brunati, I.
Andrè, V.
Della Mina, P.
Villa, A.
Greaves, M.
Biondi, A.
D'Amico, G.
Ford, A.
Cazzaniga, G.
(2014). Cytoskeletal regulatory gene expression and migratory properties of B-cell progenitors are affected by the ETV6-RUNX1 rearrangement. Mol cancer res,
Vol.12
(12),
pp. 1796-1806.
show abstract
UNLABELLED: Although the ETV6-RUNX1 fusion is a frequent initiating event in childhood leukemia, its role in leukemogenesis is only partly understood. The main impact of the fusion itself is to generate and sustain a clone of clinically silent preleukemic B-cell progenitors (BCP). Additional oncogenic hits, occurring even several years later, are required for overt disease. The understanding of the features and interactions of ETV6-RUNX1-positive cells during this "latency" period may explain how these silent cells can persist and whether they could be prone to additional genetic changes. In this study, two in vitro murine models were used to investigate whether ETV6-RUNX1 alters the cellular adhesion and migration properties of BCP. ETV6-RUNX1-expressing cells showed a significant defect in the chemotactic response to CXCL12, caused by a block in CXCR4 signaling, as demonstrated by inhibition of CXCL12-associated calcium flux and lack of ERK phosphorylation. Moreover, the induction of ETV6-RUNX1 caused changes in the expression of cell-surface adhesion molecules. The expression of genes regulating the cytoskeleton was also affected, resulting in a block of CDC42 signaling. The abnormalities described here could alter the interaction of ETV6-RUNX1 preleukemic BCP with the microenvironment and contribute to the pathogenesis of the disease. IMPLICATIONS: Alterations in the expression of cytoskeletal regulatory genes and migration properties of BCP represent early events in the evolution of the disease, from the preleukemic phase to the clinical onset, and suggest new strategies for effective eradication of leukemia..
Potter, N.E.
Greaves, M.
(2014). Cancer: Persistence of leukaemic ancestors. Nature,
Vol.506
(7488),
pp. 300-301.
Greaves, M.
(2014). Response to Jablonski and Chaplin. Proceedings of the royal society b-biological sciences,
Vol.281
(1789).
Greaves, M.
(2014). Was skin cancer a selective force for black pigmentation in early hominin evolution?. Proc biol sci,
Vol.281
(1781),
p. 20132955.
show abstract
Melanin provides a crucial filter for solar UV radiation and its genetically determined variation influences both skin pigmentation and risk of cancer. Genetic evidence suggests that the acquisition of a highly stable melanocortin 1 receptor allele promoting black pigmentation arose around the time of savannah colonization by hominins at some 1-2 Ma. The adaptive significance of dark skin is generally believed to be protection from UV damage but the pathologies that might have had a deleterious impact on survival and/or reproductive fitness, though much debated, are uncertain. Here, I suggest that data on age-associated cancer incidence and lethality in albinos living at low latitudes in both Africa and Central America support the contention that skin cancer could have provided a potent selective force for the emergence of black skin in early hominins..
Williams, C.K.
Foroni, L.
Luzzatto, L.
Saliu, I.
Levine, A.
Greaves, M.F.
(2014). Childhood leukaemia and lymphoma: African experience supports a role for environmental factors in leukaemogenesis. Ecancermedicalscience,
Vol.8,
p. 478.
show abstract
Major differences exist in the nature of leukaemia and lymphoma in low-income African children compared to those in the high-income countries. These include the absence of the peak incidence of acute lymphoblastic leukaemia (ALL) in under-five-year olds that characterizes the disease in high-income countries. Conversely, chloroma association with acute myelogenous leukaemia (CA-AML/AMML) and Burkitt's lymphoma (BL) are rare in the high-income countries. This report describes clinical and laboratory as well as epidemiological features of childhood leukaemia and lymphoma reported betwen 1982 and 1984 in the city of Ibadan, Nigeria. The observed pattern of distribution of childhood haematological malignancies in the city is more consistent with the observations of Ludwik Gross's experiments on environmental influences, such as malnutrition and infections, animal leukaemogenesis, and mirroring the consequences of the primordial pressures that have shaped human genetics and pathophysiology..
Greaves, M.
(2013). Cancer stem cells as 'units of selection'. Evol appl,
Vol.6
(1),
pp. 102-108.
show abstract
Cancer development is widely recognized to be a somatic cell evolutionary process with complex dynamics and highly variable time frames. Variant cells and descendent subclones gain competitive advantage via their fitness in relation to micro-environmental selective pressures. In this context, the 'unit' of selection is the cell, but not any cell. The so-called 'cancer stem cells' have the essential properties required to function as the key units of selection, particularly with respect to their proliferative potential and longevity. These cells drive evolutionary progression of disease and provide reservoirs for relapse or recurrence and drug resistance. They represent the prime, but elusive and moving, targets for therapeutic control..
Inaba, H.
Greaves, M.
Mullighan, C.G.
(2013). Acute lymphoblastic leukaemia. Lancet,
Vol.381
(9881),
pp. 1943-1955.
van Delft, F.W.
Mansur, M.B.
Furness, C.
Minto, L.
Irving, J.
Iqbal, S.
Noronha, E.
Colman, S.
Gribben, J.
Pombo-de-Oliviera, M.
Greaves, M.
(2013). Genetics of teenage and young adult t-cell acute lymphoblastic leukaemia. British journal of haematology,
Vol.161,
pp. 12-12.
Migliorini, G.
Fiege, B.
Hosking, F.J.
Ma, Y.
Kumar, R.
Sherborne, A.L.
da Silva Filho, M.I.
Vijayakrishnan, J.
Koehler, R.
Thomsen, H.
Irving, J.A.
Allan, J.M.
Lightfoot, T.
Roman, E.
Kinsey, S.E.
Sheridan, E.
Thompson, P.
Hoffmann, P.
Nöthen, M.M.
Mühleisen, T.W.
Eisele, L.
Zimmermann, M.
Bartram, C.R.
Schrappe, M.
Greaves, M.
Stanulla, M.
Hemminki, K.
Houlston, R.S.
(2013). Variation at 10p12 2 and 10p14 influences risk of childhood B-cell acute lymphoblastic leukemia and phenotype. Blood,
Vol.122
(19),
pp. 3298-3307.
show abstract
Acute lymphoblastic leukemia (ALL) is the major pediatric cancer diagnosed in economically developed countries with B-cell precursor (BCP)-ALL, accounting for approximately 70% of ALL. Recent genome-wide association studies (GWAS) have provided the first unambiguous evidence for common inherited susceptibility to BCP-ALL, identifying susceptibility loci at 7p12.2, 9p21.3, 10q21.2, and 14q11.2. To identify additional BCP-ALL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1658 cases and 4723 controls, with validation in 1449 cases and 1488 controls. Combined analysis identified novel loci mapping to 10p12.2 (rs10828317, odds ratio [OR] = 1.23; P = 2.30 × 10(-9)) and 10p14 marked by rs3824662 (OR = 1.31; P = 8.62 × 10(-12)). The single nucleotide polymorphism rs10828317 is responsible for the N215S polymorphism in exon 7 of PIP4K2A, and rs3824662 localizes to intron 3 of the transcription factor and putative tumor suppressor gene GATA3. The rs10828317 association was shown to be specifically associated with hyperdiploid ALL, whereas the rs3824662-associated risk was confined to nonhyperdiploid non-TEL-AML1 + ALL. The risk allele of rs3824662 was correlated with older age at diagnosis (P < .001) and significantly worse event-free survivorship (P < .0001). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to BCP-ALL and the influence of constitutional genotype on disease development..
Dobbins, S.E.
Sherborne, A.L.
Ma, Y.P.
Bardini, M.
Biondi, A.
Cazzaniga, G.
Lloyd, A.
Chubb, D.
Greaves, M.F.
Houlston, R.S.
(2013). The silent mutational landscape of infant MLL-AF4 pro-B acute lymphoblastic leukemia. Genes chromosomes cancer,
Vol.52
(10),
pp. 954-960.
show abstract
Over 90% of infants (< 1-year-old) diagnosed with leukemia have pro-B acute lymphoblastic leukemia (ALL) containing the MLL-AF4 fusion. When compared with other forms of paediatric ALL affecting later B-cell differentiation, MLL-AF4 pro-B is associated with a dismal prognosis with a typical 5-year disease-free survival of <20%. MLL-AF4 may be sufficient on its own for leukemogenesis or the gene-fusion product may alternatively predispose transformed cells to global genetic instability, enhancing the acquisition of additional key mutations. To gain insight into the genomic landscape of infant MLL-AF4 pro-B ALL we performed whole genome sequencing of diagnostic leukemic blasts and matched germline samples from three MLL-AF4 pro-B ALL infants. Our analysis revealed few somatic changes (copy number abnormalities, loss of heterozygosity, or single nucleotide variants), demonstrating that only a very small number of mutations are necessary to generate infant MLL-leukemia..
Potter, N.E.
Ermini, L.
Papaemmanuil, E.
Cazzaniga, G.
Vijayaraghavan, G.
Titley, I.
Ford, A.
Campbell, P.
Kearney, L.
Greaves, M.
(2013). Single-cell mutational profiling and clonal phylogeny in cancer. Genome res,
Vol.23
(12),
pp. 2115-2125.
show abstract
The development of cancer is a dynamic evolutionary process in which intraclonal, genetic diversity provides a substrate for clonal selection and a source of therapeutic escape. The complexity and topography of intraclonal genetic architectures have major implications for biopsy-based prognosis and for targeted therapy. High-depth, next-generation sequencing (NGS) efficiently captures the mutational load of individual tumors or biopsies. But, being a snapshot portrait of total DNA, it disguises the fundamental features of subclonal variegation of genetic lesions and of clonal phylogeny. Single-cell genetic profiling provides a potential resolution to this problem, but methods developed to date all have limitations. We present a novel solution to this challenge using leukemic cells with known mutational spectra as a tractable model. DNA from flow-sorted single cells is screened using multiplex targeted Q-PCR within a microfluidic platform allowing unbiased single-cell selection, high-throughput, and comprehensive analysis for all main varieties of genetic abnormalities: chimeric gene fusions, copy number alterations, and single-nucleotide variants. We show, in this proof-of-principle study, that the method has a low error rate and can provide detailed subclonal genetic architectures and phylogenies..
Greaves, M.
(2013). Clonal expansion in B-CLL: fungal drivers or self-service?. J exp med,
Vol.210
(1),
pp. 1-3.
show abstract
Relatively few cancers arise in mature, differentiated cells. The propensity of mature B cells to transform has been linked to their longevity and proliferative potential, and stimulation of the B cell receptor (BCR) by cognate antigen may promote the transformation process. A study in this issue (Hoogeboom et al.) lends support to this notion, showing that cancer cells from a subset of patients with chronic lymphocytic leukemia (CLL) express a BCR specific for a sugar expressed by commensal yeast species. Another study, in contrast, suggests that B-CLL cells uniquely acquire the ability to signal in the complete absence of ligand..
Greaves, M.
(2013). Return of the malingering mutants. Br j cancer,
Vol.109
(6),
pp. 1391-1393.
Nangalia, J.
Massie, C.E.
Baxter, E.J.
Nice, F.L.
Gundem, G.
Wedge, D.C.
Avezov, E.
Li, J.
Kollmann, K.
Kent, D.G.
Aziz, A.
Godfrey, A.L.
Hinton, J.
Martincorena, I.
Van Loo, P.
Jones, A.V.
Guglielmelli, P.
Tarpey, P.
Harding, H.P.
Fitzpatrick, J.D.
Goudie, C.T.
Ortmann, C.A.
Loughran, S.J.
Raine, K.
Jones, D.R.
Butler, A.P.
Teague, J.W.
O'Meara, S.
McLaren, S.
Bianchi, M.
Silber, Y.
Dimitropoulou, D.
Bloxham, D.
Mudie, L.
Maddison, M.
Robinson, B.
Keohane, C.
Maclean, C.
Hill, K.
Orchard, K.
Tauro, S.
Du, M.-.
Greaves, M.
Bowen, D.
Huntly, B.J.
Harrison, C.N.
Cross, N.C.
Ron, D.
Vannucchi, A.M.
Papaemmanuil, E.
Campbell, P.J.
Green, A.R.
(2013). Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2. New england journal of medicine,
Vol.369
(25),
pp. 2391-2405.
Alexandrov, L.B.
Nik-Zainal, S.
Wedge, D.C.
Aparicio, S.A.
Behjati, S.
Biankin, A.V.
Bignell, G.R.
Bolli, N.
Borg, A.
Borresen-Dale, A.-.
Boyault, S.
Burkhardt, B.
Butler, A.P.
Caldas, C.
Davies, H.R.
Desmedt, C.
Eils, R.
Eyfjord, J.E.
Foekens, J.A.
Greaves, M.
Hosoda, F.
Hutter, B.
Ilicic, T.
Imbeaud, S.
Imielinsk, M.
Jaeger, N.
Jones, D.T.
Jones, D.
Knappskog, S.
Kool, M.
Lakhani, S.R.
Lopez-Otin, C.
Martin, S.
Munshi, N.C.
Nakamura, H.
Northcott, P.A.
Pajic, M.
Papaemmanuil, E.
Paradiso, A.
Pearson, J.V.
Puente, X.S.
Raine, K.
Ramakrishna, M.
Richardson, A.L.
Richter, J.
Rosenstiel, P.
Schlesner, M.
Schumacher, T.N.
Span, P.N.
Teague, J.W.
Totoki, Y.
Tutt, A.N.
Valdes-Mas, R.
van Buuren, M.M.
van 't Veer, L.
Vincent-Salomon, A.
Waddell, N.
Yates, L.R.
Zucman-Rossi, J.
Futreal, P.A.
McDermott, U.
Lichter, P.
Meyerson, M.
Grimmond, S.M.
Siebert, R.
Campo, E.
Shibata, T.
Pfister, S.M.
Campbell, P.J.
Stratton, M.R.
Genome, A.P.
Consortium, I.C.
Consortium, I.C.
PedBrain, I.C.
(2013). Signatures of mutational processes in human cancer. Nature,
Vol.500
(7463),
pp. 415-+.
Ma, Y.
Dobbins, S.E.
Sherborne, A.L.
Chubb, D.
Galbiati, M.
Cazzaniga, G.
Micalizzi, C.
Tearle, R.
Lloyd, A.L.
Hain, R.
Greaves, M.
Houlston, R.S.
(2013). Developmental timing of mutations revealed by whole-genome sequencing of twins with acute lymphoblastic leukemia. Proc natl acad sci u s a,
Vol.110
(18),
pp. 7429-7433.
show abstract
Acute lymphoblastic leukemia (ALL) is the major pediatric cancer. At diagnosis, the developmental timing of mutations contributing critically to clonal diversification and selection can be buried in the leukemia's covert natural history. Concordance of ALL in monozygotic, monochorionic twins is a consequence of intraplacental spread of an initiated preleukemic clone. Studying monozygotic twins with ALL provides a unique means of uncovering the timeline of mutations contributing to clonal evolution, pre- and postnatally. We sequenced the whole genomes of leukemic cells from two twin pairs with ALL to comprehensively characterize acquired somatic mutations in ALL, elucidating the developmental timing of all genetic lesions. Shared, prenatal, coding-region single-nucleotide variants were limited to the putative initiating lesions. All other nonsynonymous single-nucleotide variants were distinct between tumors and, therefore, secondary and postnatal. These changes occurred in a background of noncoding mutational changes that were almost entirely discordant in twin pairs and likely passenger mutations acquired during leukemic cell proliferation..
Enciso-Mora, V.
Hosking, F.J.
Sheridan, E.
Kinsey, S.E.
Lightfoot, T.
Roman, E.
Irving, J.A.
Tomlinson, I.P.
Allan, J.M.
Taylor, M.
Greaves, M.
Houlston, R.S.
(2012). Common genetic variation contributes significantly to the risk of childhood B-cell precursor acute lymphoblastic leukemia. Leukemia,
Vol.26
(10),
pp. 2212-2215.
show abstract
Recent genome-wide association studies (GWAS) have provided the first unambiguous evidence that common genetic variation influences the risk of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), identifying risk single-nucleotide polymorphisms (SNPs) localizing to 7p12.2, 9p21.3, 10q21.2 and 14q11.2. The testing of SNPs individually for an association in GWA studies necessitates the imposition of a very stringent P-value to address the issue of multiple testing. While this reduces false positives, real associations may be missed and therefore any estimate of the total heritability will be negatively biased. Using GWAS data on 823 BCP-ALL cases by considering all typed SNPs simultaneously, we have calculated that 24% of the total variation in BCP-ALL risk is accounted for common genetic variation (95% confidence interval 6-42%). Our findings provide support for a polygenic basis for susceptibility to BCP-ALL and have wider implications for future searches for novel disease-causing risk variants..
van Delft, F.
Furness, C.
Minto, L.
Irving, J.
Colman, S.
Greaves, M.
(2012). DISTINCT GENETICS OF TEENAGE AND YOUNG ADULT ACUTE LYMPHOBLASTIC LEUKAEMIA. Pediatric blood & cancer,
Vol.59
(6),
pp. 1028-1028.
Greaves, M.
Maley, C.C.
(2012). Clonal evolution in cancer. Nature,
Vol.481
(7381),
pp. 306-313.
show abstract
Cancers evolve by a reiterative process of clonal expansion, genetic diversification and clonal selection within the adaptive landscapes of tissue ecosystems. The dynamics are complex, with highly variable patterns of genetic diversity and resulting clonal architecture. Therapeutic intervention may destroy cancer clones and erode their habitats, but it can also inadvertently provide a potent selective pressure for the expansion of resistant variants. The inherently Darwinian character of cancer is the primary reason for this therapeutic failure, but it may also hold the key to more effective control..
Greaves, M.
(2011). Leukemogenesis and ageing: 'fit for transformation'?. Aging-us,
Vol.3
(2),
pp. 79-2.
Mansur, M.B.
Ford, A.M.
van Delft, F.W.
Gonzalez, D.
Emerenciano, M.
Maia, R.C.
Greaves, M.
Pombo-de-Oliveira, M.S.
(2011). Occurrence of identical NOTCH1 mutation in non-twinned sisters with T-cell acute lymphoblastic leukemia. Leukemia,
Vol.25
(8),
pp. 1368-4.
Greaves, M.
(2011). Genetic Architecture of Leukaemia. Annals of hematology,
Vol.90,
pp. S33-2.
Greaves, M.
(2011). Cancer stem cells renew their impact. Nature medicine,
Vol.17
(9),
pp. 1046-3.
Hosking, F.J.
Leslie, S.
Dilthey, A.
Moutsianas, L.
Wang, Y.
Dobbins, S.E.
Papaemmanuil, E.
Sheridan, E.
Kinsey, S.E.
Lightfoot, T.
Roman, E.
Irving, J.A.
Allan, J.M.
Taylor, M.
Greaves, M.
McVean, G.
Houlston, R.S.
(2011). MHC variation and risk of childhood B-cell precursor acute lymphoblastic leukemia. Blood,
Vol.117
(5),
pp. 1633-1640.
show abstract
A role for specific human leukocyte antigen (HLA) variants in the etiology of childhood acute lymphoblastic leukemia (ALL) has been extensively studied over the last 30 years, but no unambiguous association has been identified. To comprehensively study the relationship between genetic variation within the 4.5 Mb major histocompatibility complex genomic region and precursor B-cell (BCP) ALL risk, we analyzed 1075 observed and 8176 imputed single nucleotide polymorphisms and their related haplotypes in 824 BCP-ALL cases and 4737 controls. Using these genotypes we also imputed both common and rare alleles at class I (HLA-A, HLA-B, and HLA-C) and class II (HLA-DRB1, HLA-DQA1, and HLA-DQB1) HLA loci. Overall, we found no statistically significant association between variants and BCP-ALL risk. We conclude that major histocompatibility complex-defined variation in immune-mediated response is unlikely to be a major risk factor for BCP-ALL..
Torrano, V.
Procter, J.
Cardus, P.
Greaves, M.
Ford, A.M.
(2011). ETV6-RUNX1 promotes survival of early B lineage progenitor cells via a dysregulated erythropoietin receptor. Blood,
Vol.118
(18),
pp. 4910-4918.
Montes, R.
Ayllon, V.
Gutierrez-Aranda, I.
Prat, I.
Carmen Hernandez-Lamas, M.
Ponce, L.
Bresolin, S.
Te Kronnie, G.
Greaves, M.
Bueno, C.
Menendez, P.
(2011). Enforced expression of MLL-AF4 fusion in cord blood CD34+ cells enhances the hematopoietic repopulating cell function and clonogenic potential but is not sufficient to initiate leukemia. Blood,
Vol.117
(18),
pp. 4746-13.
Greaves, M.
Colman, S.M.
Kearney, L.
Ford, A.M.
(2011). Fusion genes in cord blood. Blood,
Vol.117
(1),
pp. 369-4.
Sherborne, A.L.
Hemminki, K.
Kumar, R.
Bartram, C.R.
Stanulla, M.
Schrappe, M.
Petridou, E.
Semsei, A.F.
Szalai, C.
Sinnett, D.
Krajinovic, M.
Healy, J.
Lanciotti, M.
Dufour, C.
Indaco, S.
El-Ghouroury, E.A.
Sawangpanich, R.
Hongeng, S.
Pakakasama, S.
Gonzalez-Neira, A.
Ugarte, E.L.
Leal, V.P.
Espinoza, J.P.
Kamel, A.M.
Ebid, G.T.
Radwan, E.R.
Yalin, S.
Yalin, E.
Berkoz, M.
Simpson, J.
Roman, E.
Lightfoot, T.
Hosking, F.J.
Vijayakrishnan, J.
Greaves, M.
Houlston, R.S.
(2011). Rationale for an international consortium to study inherited genetic susceptibility to childhood acute lymphoblastic leukemia. Haematologica,
Vol.96
(7),
pp. 1049-1054.
show abstract
Acute lymphoblastic leukemia is the major pediatric cancer in developed countries. To date most association studies of acute lymphoblastic leukemia have been based on the candidate gene approach and have evaluated a restricted number of polymorphisms. Such studies have served to highlight difficulties in conducting statistically and methodologically rigorous investigations into acute lymphoblastic leukemia risk. Recent genome-wide association studies of childhood acute lymphoblastic leukemia have provided robust evidence that common variation at four genetic loci confers a modest increase in risk. The accumulated experience to date and relative lack of success of initial efforts to identify novel acute lymphoblastic leukemia predisposition loci emphasize the need for alternative study designs and methods. The International Childhood Acute Lymphoblastic Leukaemia Genetics Consortium includes 12 research groups in Europe, Asia, the Middle East and the Americas engaged in studying the genetics of acute lymphoblastic leukemia. The initial goal of this consortium is to identify and characterize low-penetrance susceptibility variants for acute lymphoblastic leukemia through association-based analyses. Efforts to develop genome-wide association studies of acute lymphoblastic leukemia, in terms of both sample size and single nucleotide polymorphism coverage, and to increase the number of single nucleotide polymorphisms taken forward to large-scale replication should lead to the identification of additional novel risk variants for acute lymphoblastic leukemia. Ethnic differences in the risk of acute lymphoblastic leukemia are well recognized and thus in assessing the interplay between inherited and non-genetic risk factors, analyses using different population cohorts with different incidence rates are likely to be highly informative. Given that the frequency of many acute lymphoblastic leukemia subgroups is small, identifying differential effects will realistically only be possible through multi-center pooled analyses. Here, we review the rationale for identifying genetic risk variants for acute lymphoblastic leukemia and our proposed strategy for establishing the International Childhood Acute Lymphoblastic Leukaemia Genetics Consortium..
Alvares, C.L.
Schenk, T.
Hulkki, S.
Min, T.
Vijayaraghavan, G.
Yeung, J.
Gonzalez, D.
So, C.W.
Greaves, M.
Titley, I.
Bartolovic, K.
Morgan, G.
(2011). Tyrosine kinase inhibitor insensitivity of non-cycling CD34+ human acute myeloid leukaemia cells with FMS-like tyrosine kinase 3 mutations. Br j haematol,
Vol.154
(4),
pp. 457-465.
show abstract
The efficacy of tyrosine kinase (TK) inhibitors on non-cycling acute myeloid leukaemia (AML) cells, previously shown to have potent tumourigenic potential, is unknown. This pilot study describes the first attempt to characterize non-cycling cells from a small series of human FMS-like tyrosine kinase 3 (FLT3) mutation positive samples. CD34+ AML cells from patients with FLT3 mutation positive AML were cultured on murine stroma. In expansion cultures, non-cycling cells were found to retain CD34+ expression in contrast to dividing cells. Leukaemic gene rearrangements could be detected in non-cycling cells, indicating their leukaemic origin. Significantly, the FLT3-internal tandem duplication (ITD) mutation was found in the non-cycling fraction of four out of five cases. Exposure to the FLT3-directed inhibitor TKI258 clearly inhibited the growth of AML CD34+ cells in short-term cultures and colony-forming unit assays. Crucially, non-cycling cells were not eradicated, with the exception of one case, which exhibited exquisite sensitivity to the compound. Moreover, in longer-term cultures, TKI258-treated non-cycling cells showed no growth impairment compared to treatment-naive non-cycling cells. These findings suggest that non-cycling cells in AML may constitute a disease reservoir that is resistant to TK inhibition. Further studies with a larger sample size and other inhibitors are warranted..
van Delft, F.W.
Horsley, S.
Colman, S.
Anderson, K.
Bateman, C.
Kempski, H.
Zuna, J.
Eckert, C.
Saha, V.
Kearney, L.
Ford, A.
Greaves, M.
(2011). Clonal origins of relapse in ETV6-RUNX1 acute lymphoblastic leukemia. Blood,
Vol.117
(23),
pp. 6247-8.
Waugh, E.M.
Jarrett, R.F.
Shield, L.
Montgomery, D.
Dean, R.T.
Mitchell, A.
Greaves, M.F.
Gallagher, A.
(2011). The retrovirus XMRV is not directly involved in the pathogenesis of common types of lymphoid malignancy. Cancer epidemiol biomarkers prev,
Vol.20
(10),
pp. 2232-2236.
show abstract
BACKGROUND: A novel retrovirus, xenotropic murine leukemia virus-related virus (XMRV), has been detected in prostate cancer samples and in peripheral blood mononuclear cells (PBMC) from patients with chronic fatigue syndrome. In addition, the virus has been identified in PBMCs from healthy controls. These data suggest that XMRV is circulating in the human population. XMRV is closely related to murine leukemia viruses, which cause lymphoid malignancies in mice. The aim of this study was to determine whether XMRV is directly associated with common forms of human lymphoma or leukemia. METHODS: DNA samples from 368 patients with lymphoid malignancies and 139 patients with benign lymphadenopathy or other malignant disease were screened for XMRV, using three specific and sensitive quantitative PCR assays. RESULTS: XMRV was not detected in any sample using any of the three assays. CONCLUSIONS: The data suggest that this virus is not directly involved in the pathogenesis of common types of lymphoid malignancy and that XMRV is not a prevalent blood borne infection, at least in the United Kingdom. IMPACT: There is no evidence that XMRV is associated with lymphoid malignancies, and further studies should resolve inconsistencies in results of studies examining XMRV prevalence..
Cazzaniga, G.
van Delft, F.W.
Lo Nigro, L.
Ford, A.M.
Score, J.
Iacobucci, I.
Mirabile, E.
Taj, M.
Colman, S.M.
Biondi, A.
Greaves, M.
(2011). Developmental origins and impact of BCR-ABL1 fusion and IKZF1 deletions in monozygotic twins with Ph+ acute lymphoblastic leukemia. Blood,
Vol.118
(20),
pp. 5559-5564.
show abstract
The timing and developmental sequence of events for BCR-ABL1(+) acute lymphoblastic leukemia (ALL), usually associated with IKAROS (IKZF1) deletions, are unknown. We assessed the status of BCR-ABL1 and IKZF1 genes in 2 pairs of monozygotic twins, one pair concordant, the other discordant for Philadelphia chromosome positive (Ph(+)) ALL. The twin pair concordant for ALL shared identical BCR-ABL1 genomic sequence indicative of monoclonal, in utero origin. One twin had IKZF1 deletion and died after transplantation. The other twin had hyperdiploidy, no IKZF1 deletion, and is still in remission 8 years after transplantation. In the twin pair discordant for ALL, neonatal blood spots from both twins harbored the same clonotypic BCR-ABL1 sequence. Low level BCR-ABL1(+) cells were present in the healthy co-twin but lacked the IKZF1 deletion present in the other twin's leukemic cells. The twin with ALL relapsed and died after transplantation. The co-twin remains healthy and leukemia free. These data show that in childhood Ph(+) ALL, BCR-ABL1 gene fusion can be a prenatal and possibly initiating genetic event. In the absence of additional, secondary changes, the leukemic clone remains clinically silent. IKZF1 is a secondary and probable postnatal mutation in these cases, and as a recurrent but alternative copy number change is associated with poor prognosis..
Anderson, K.
Lutz, C.
van Delft, F.W.
Bateman, C.M.
Guo, Y.
Colman, S.M.
Kempski, H.
Moorman, A.V.
Titley, I.
Swansbury, J.
Kearney, L.
Enver, T.
Greaves, M.
(2011). Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature,
Vol.469
(7330),
pp. 356-7.
van der Weyden, L.
Giotopoulos, G.
Rust, A.G.
Matheson, L.S.
van Delft, F.W.
Kong, J.
Corcoran, A.E.
Greaves, M.F.
Mullighan, C.G.
Huntly, B.J.
Adams, D.J.
(2011). Modeling the evolution of ETV6-RUNX1-induced B-cell precursor acute lymphoblastic leukemia in mice. Blood,
Vol.118
(4),
pp. 1041-11.
Cazzaniga, G.
Van Delft, F.W.
Colman, S.
Score, J.
Kempski, H.
Taj, M.
Ford, A.
Biondi, A.
Greaves, M.
(2010). SEQUENTIAL ACQUISITION OF BCR-ABL1 FUSION AND IKAROS DELETION IN PHILADELPHIA CHROMOSOME POSITIVE ALL. Pediatric blood & cancer,
Vol.55
(5),
pp. 833-1.
Cazzaniga, G.
Bardini, M.
Wittman, L.
Corral, L.
Lo Nigro, L.
Ma, Z.
De Rossi, G.
Basso, G.
Greaves, M.
Biondi, A.
Jacobsen, S.E.
(2010). OLIGOCLONAL ORIGIN OF FUNCTIONALLY DISTINCT LEUKEMIC STEM CELLS IN INFANT ACUTE LYMPHOBLASTIC LEUKEMIA. Pediatric blood & cancer,
Vol.55
(5),
pp. 794-1.
Hosking, F.J.
Papaemmanuil, E.
Sheridan, E.
Kinsey, S.E.
Lightfoot, T.
Roman, E.
Irving, J.A.
Allan, J.M.
Taylor, M.
Tomlinson, I.P.
Greaves, M.
Houlston, R.S.
(2010). Genome-wide homozygosity signatures and childhood acute lymphoblastic leukemia risk. Blood,
Vol.115
(22),
pp. 4472-4477.
show abstract
Recent studies have reported that regions of homozygosity (ROH) in the genome are detectable in outbred populations and can be associated with an increased risk of malignancy. To examine whether homozygosity is associated with an increased risk of developing childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), we analyzed 824 ALL cases and 2398 controls genotyped for 292 200 tagging SNPs. Across the genome, cumulative distribution of ROH was not significantly different between cases and controls. Four common ROH at 10p11.2-10q11.21, 1p31.1, 19p13.2-3, and 20q11.1-23 were, however, associated with ALL risk at P less than .01 (including 1 ROH to which the erythropoietin receptor [EPOR] gene maps, P = .005) but were nonsignificant after adjusting for multiple testing. Our findings make it unlikely that levels of measured homozygosity, caused by autozygosity, uniparental isodisomy, or hemizygosity, play a major role in defining BCP-ALL risk in predominantly outbred populations..
Prasad, R.B.
Hosking, F.J.
Vijayakrishnan, J.
Papaemmanuil, E.
Koehler, R.
Greaves, M.
Sheridan, E.
Gast, A.
Kinsey, S.E.
Lightfoot, T.
Roman, E.
Taylor, M.
Pritchard-Jones, K.
Stanulla, M.
Schrappe, M.
Bartram, C.R.
Houlston, R.S.
Kumar, R.
Hemminki, K.
(2010). Verification of the susceptibility loci on 7p12 2, 10q21 2, and 14q11 2 in precursor B-cell acute lymphoblastic leukemia of childhood. Blood,
Vol.115
(9),
pp. 1765-3.
Greaves, M.
(2010). Cancer stem cells: back to Darwin?. Semin cancer biol,
Vol.20
(2),
pp. 65-70.
show abstract
Current models of cancer propagation or 'stem' cells pay scant attention to the evolutionary dynamics of cancer or to the underlying genetic, mutational drivers. Recent genetic studies on acute lymphoblastic leukaemia at the single cell level reveal a complex non-linear, branching clonal architecture-with sub-clones having distinctive genetic signatures. Most cancers appropriately interrogated are found to have intra-clonal genetic heterogeneity indicative of divergent clonal evolution. These data further suggest that clonal architecture might be driven by genetic heterogeneity of propagating or 'stem' cells. When assayed for leukaemic regeneration in NOD/SCID/gamma mice, genetically diverse 'stem' cells read-out, broadly reflecting the clonal architecture. This has suggested a 'back to Darwin' model for cancer propagation. In this, cells with self-renewal potency or 'stem-ness' provide genetically diverse units of evolutionary selection in cancer progression. The model has significant implications for targeted cancer therapy..
Sherborne, A.L.
Hosking, F.J.
Prasad, R.B.
Kumar, R.
Koehler, R.
Vijayakrishnan, J.
Papaemmanuil, E.
Bartram, C.R.
Stanulla, M.
Schrappe, M.
Gast, A.
Dobbins, S.E.
Ma, Y.
Sheridan, E.
Taylor, M.
Kinsey, S.E.
Lightfoot, T.
Roman, E.
Irving, J.A.
Allan, J.M.
Moorman, A.V.
Harrison, C.J.
Tomlinson, I.P.
Richards, S.
Zimmermann, M.
Szalai, C.
Semsei, A.F.
Erdelyi, D.J.
Krajinovic, M.
Sinnett, D.
Healy, J.
Gonzalez Neira, A.
Kawamata, N.
Ogawa, S.
Koeffler, H.P.
Hemminki, K.
Greaves, M.
Houlston, R.S.
(2010). Variation in CDKN2A at 9p21 3 influences childhood acute lymphoblastic leukemia risk. Nat genet,
Vol.42
(6),
pp. 492-494.
show abstract
Using data from a genome-wide association study of 907 individuals with childhood acute lymphoblastic leukemia (cases) and 2,398 controls and with validation in samples totaling 2,386 cases and 2,419 controls, we have shown that common variation at 9p21.3 (rs3731217, intron 1 of CDKN2A) influences acute lymphoblastic leukemia risk (odds ratio = 0.71, P = 3.01 x 10(-11)), irrespective of cell lineage..
Bateman, C.M.
Colman, S.M.
Chaplin, T.
Young, B.D.
Eden, T.O.
Bhakta, M.
Gratias, E.J.
van Wering, E.R.
Cazzaniga, G.
Harrison, C.J.
Hain, R.
Ancliff, P.
Ford, A.M.
Kearney, L.
Greaves, M.
(2010). Acquisition of genome-wide copy number alterations in monozygotic twins with acute lymphoblastic leukemia. Blood,
Vol.115
(17),
pp. 3553-3558.
show abstract
Chimeric fusion genes are highly prevalent in childhood acute lymphoblastic leukemia (ALL) and are mostly prenatal, early genetic events in the evolutionary trajectory of this cancer. ETV6-RUNX1-positive ALL also has multiple ( approximately 6 per case) copy number alterations (CNAs) as revealed by genome-wide single-nucleotide polymorphism arrays. Recurrent CNAs are probably "driver" events contributing critically to clonal diversification and selection, but at diagnosis, their developmental timing is "buried" in the leukemia's covert natural history. This conundrum can be resolved with twin pairs. We identified and compared CNAs in 5 pairs of monozygotic twins with concordant ETV6-RUNX1-positive ALL and 1 pair discordant for ETV6-RUNX1 positive ALL. We compared, within each pair, CNAs classified as potential "driver" or "passenger" mutations based upon recurrency and, where known, gene function. An average of 5.1 (range 3-11) CNAs (excluding immunoglobulin/T-cell receptor alterations) were identified per case. All "driver" CNAs (total of 32) were distinct within each of the 5 twin pairs with concordant ALL. "Driver" CNAs in another twin with ALL were all absent in the shared ETV6-RUNX1-positive preleukemic clone of her healthy co-twin. These data place all "driver" CNAs secondary to the prenatal gene fusion event and most probably postnatal in the sequential, molecular pathogenesis of ALL..
Zuna, J.
Burjanivova, T.
Mejstrikova, E.
Zemanova, Z.
Muzikova, K.
Meyer, C.
Horsley, S.W.
Kearney, L.
Colman, S.
Ptoszkova, H.
Marschalek, R.
Hrusak, O.
Stary, J.
Greaves, M.
Trka, J.
(2009). Covert Preleukemia Driven by MLL Gene Fusion. Genes chromosomes & cancer,
Vol.48
(1),
pp. 98-10.
Orjuela, M.
Ford, A.
Perera, F.
Tang, D.
Liu, X.
Cujar, C.
Cardus, P.
Procter, J.
Siebert, A.
Warburton, D.
Greaves, M.
(2009). Presence of ETV6-RUNX1 (TEL-AML1) in healthy children is associated with increased IGF1 and aberrations in chromosome 12. Cancer research,
Vol.69.
Greaves, M.
Buffler, P.A.
(2009). Infections in early life and risk of childhood ALL. British journal of cancer,
Vol.100
(5),
pp. 863-1.
Ford, A.M.
Palmi, C.
Bueno, C.
Hong, D.
Cardus, P.
Knight, D.
Cazzaniga, G.
Enver, T.
Greaves, M.
(2009). The TEL-AML1 leukemia fusion gene dysregulates the TGF-beta pathway in early B lineage progenitor cells. J clin invest,
Vol.119
(4),
pp. 826-836.
show abstract
Chromosome translocation to generate the TEL-AML1 (also known as ETV6-RUNX1) chimeric fusion gene is a frequent and early or initiating event in childhood acute lymphoblastic leukemia (ALL). Our starting hypothesis was that the TEL-AML1 protein generates and maintains preleukemic clones and that conversion to overt disease requires secondary genetic changes, possibly in the context of abnormal immune responses. Here, we show that a murine B cell progenitor cell line expressing inducible TEL-AML1 proliferates at a slower rate than parent cells but is more resistant to further inhibition of proliferation by TGF-beta. This facilitates the competitive expansion of TEL-AML1-expressing cells in the presence of TGF-beta. Further analysis indicated that TEL-AML1 binds to a principal TGF-beta signaling target, Smad3, and compromises its ability to activate target promoters. In mice expressing a TEL-AML1 transgene, early, pre-pro-B cells were increased in number and also showed reduced sensitivity to TGF-beta-mediated inhibition of proliferation. Moreover, expression of TEL-AML1 in human cord blood progenitor cells led to the expansion of a candidate preleukemic stem cell population that had an early B lineage phenotype (CD34+CD38-CD19+) and a marked growth advantage in the presence of TGF-beta. Collectively, these data suggest a plausible mechanism by which dysregulated immune responses to infection might promote the malignant evolution of TEL-AML1-expressing preleukemic clones..
Catalina, P.
Bueno, C.
Montes, R.
Nieto, A.
Ligero, G.
Sanchez, L.
Jara, M.
Rosillo, A.
Orfao, A.
Cigudosa, J.
Hovatta, O.
Greaves, M.
Menendez, P.
(2009). Genetic stability of human embryonic stem cells: A first-step toward the development of potential hESC-based systems for modeling childhood leukemia. Leukemia research,
Vol.33
(7),
pp. 980-11.
Papaemmanuil, E.
Hosking, F.J.
Vijayakrishnan, J.
Price, A.
Olver, B.
Sheridan, E.
Kinsey, S.E.
Lightfoot, T.
Roman, E.
Irving, J.A.
Allan, J.M.
Tomlinson, I.P.
Taylor, M.
Greaves, M.
Houlston, R.S.
(2009). Loci on 7p12 2, 10q21 2 and 14q11 2 are associated with risk of childhood acute lymphoblastic leukemia. Nat genet,
Vol.41
(9),
pp. 1006-1010.
show abstract
full text
To identify risk variants for childhood acute lymphoblastic leukemia (ALL), we conducted a genome-wide association study of two case-control series, analyzing the genotypes with respect to 291,423 tagging SNPs in a total of 907 ALL cases and 2,398 controls. We identified risk loci for ALL at 7p12.2 (IKZF1, rs4132601, odds ratio (OR) = 1.69, P = 1.20 x 10(-19)), 10q21.2 (ARID5B, rs7089424, OR = 1.65, P = 6.69 x 10(-19)) and 14q11.2 (CEBPE, rs2239633, OR = 1.34, P = 2.88 x 10(-7)). The 10q21.2 (ARID5B) risk association appears to be selective for the subset of B-cell precursor ALL with hyperdiploidy. These data show that common low-penetrance susceptibility alleles contribute to the risk of developing childhood ALL and provide new insight into disease causation of this specific hematological cancer. Notably, all three risk variants map to genes involved in transcriptional regulation and differentiation of B-cell progenitors..
Kearney, L.
De Castro, D.G.
Yeung, J.
Procter, J.
Horsley, S.W.
Eguchi-Ishimae, M.
Bateman, C.M.
Anderson, K.
Chaplin, T.
Young, B.D.
Harrison, C.J.
Kempski, H.
So, C.W.
Ford, A.M.
Greaves, M.
(2009). Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemia. Blood,
Vol.113
(3),
pp. 646-3.
Isoda, T.
Ford, A.M.
Tomizawa, D.
van Delft, F.W.
de Castro, D.G.
Mitsuiki, N.
Score, J.
Taki, T.
Morio, T.
Takagi, M.
Saji, H.
Greaves, M.
Mizutani, S.
(2009). Immunologically silent cancer clone transmission from mother to offspring. Proceedings of the national academy of sciences of the united states of america,
Vol.106
(42),
pp. 17882-4.
Greaves, M.
(2009). Darwin and evolutionary tales in leukemia The Ham-Wasserman Lecture. Hematology am soc hematol educ program,
,
pp. 3-12.
show abstract
All cancers evolve by a process of genetic diversification and "natural selection" akin to the process first described by Charles Darwin for species evolution. The evolutionary, natural history of childhood acute lymphoblastic leukemia (ALL) is almost entirely covert, clinically silent and well advanced by the point of diagnosis. It has, however, been possible to backtrack this process by molecular scrutiny of appropriate clinical samples: (i) leukemic clones in monozygotic twins that are either concordant or discordant for ALL; (ii) archived neonatal blood spots or Guthrie cards from individuals who later developed leukemia; and (iii) stored, viable cord blood cells. These studies indicate prenatal initiation of leukemia by chromosome translocation and gene fusion (or hyperdiploidy) and the post-natal acquisition of multiple, gene copy number alterations (CNAs), mostly deletions. The prenatal or first "hit" occurs very commonly, exceeding the clinical rate of ALL by some 100x and indicating a low rate of penetrance or evolutionary progression. The acquisition of the critical, secondary CNAs requires some Darwinian selective advantage to expand numbers of cells at risk, and the cytokine TGF beta is able to exercise this function. The clonal architecture of ALL has been investigated by single cell analysis with multicolor probes to mutant genes. The data reveal not a linear sequence of mutation acquisition with clonal succession but rather considerable complexity with a tree-like or branching structure of genetically distinct subclones very reminiscent of Darwin's original 1837 evolutionary divergence diagram. This evolutionary pattern has important implications for stem cells in ALL, for the origins of relapse and for therapeutic targeting..
Eguchi-Ishimae, M.
Eguchi, M.
Kempski, H.
Greaves, M.
(2008). NOTCH1 mutation can be an early, prenatal genetic event in T-ALL. Blood,
Vol.111
(1),
pp. 376-3.
Taylor, M.
Harrison, C.
Eden, T.
Birch, J.
Greaves, M.
Lightfoot, T.
Hussain, A.
(2008). HLA-DPB1 supertype-associated protection from childhood leukaemia: relationship to leukaemia karyotype and implications for prevention. Cancer immunology immunotherapy,
Vol.57
(1),
pp. 53-9.
Horsley, S.W.
Colman, S.
McKinley, M.
Bateman, C.M.
Jenney, M.
Chaplin, T.
Young, B.D.
Greaves, M.
Kearney, L.
(2008). Genetic lesions in a preleukemic aplasia phase in a child with acute lymphoblastic leukemia. Genes chromosomes cancer,
Vol.47
(4),
pp. 333-340.
show abstract
In a small fraction ( approximately 2%) of cases of childhood acute lymphoblastic leukemia (ALL) clinical presentation of leukemia is preceded, some 2-9 months earlier, by a transient, remitting phase of nonclassical aplastic anemia, usually in connection with infection. The potential "preleukemic" nature of this prodromal phase has not been fully explored. We have retrospectively analyzed the blood and bone marrow of a child who presented with aplastic anemia 9 months before the development of ETV6-RUNX1 fusion gene positive ALL. High resolution SNP genotyping arrays identified 11 regions of loss of heterozygosity, with and without concurrent copy number changes, at the presentation of ALL. In all cases of copy number change, the deletion or gain identified by single nucleotide polymorphism (SNP) analysis was confirmed in the ALL blasts by FISH. Retrospective analysis of aplastic phase bone marrow showed that the ETV6-RUNX1 fusion was present along with all of the additional genetic changes assessed, albeit subclonal to ETV6-RUNX1. These data identify for the first time the leukemic genotype of an aplasia preceding clinical ALL and indicate that multiple secondary genetic abnormalities can contribute to a dominant subclone several months before a diagnosis of ALL. These data have implications for the biology of ALL and for management of similar patients..
Taylor, G.M.
Hussain, A.
Lightfoot, T.J.
Birch, J.M.
Eden, T.O.
Greaves, M.F.
(2008). HLA-associated susceptibility to childhood B-cell precursor ALL: definition and role of HLA-DPB1 supertypes. British journal of cancer,
Vol.98
(6),
pp. 1125-7.
Hong, D.
Gupta, R.
Ancliff, P.
Atzberger, A.
Brown, J.
Soneji, S.
Green, J.
Colman, S.
Piacibello, W.
Buckle, V.
Tsuzuki, S.
Greaves, M.
Enver, T.
(2008). Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia. Science,
Vol.319
(5861),
pp. 336-4.
Gowaty, P.A.
Serageldin, I.
Persson, P.-.
Eldredge, N.
Lynch, M.
Nei, M.
Kutschera, U.
Akyol, M.
Nesse, R.
Greaves, M.
(2008). Darwin 200: Great expectations. Nature,
Vol.456
(7220),
pp. 317-2.
Bueno, C.
Lopes, L.F.
Greaves, M.
Menendez, P.
(2007). Toward development of a novel NOD/SCID-based in vivo strategy to model multiple myeloma pathogenesis. Experimental hematology,
Vol.35
(10),
pp. 1477-2.
Roman, E.
Simpson, J.
Ansell, P.
Kinsey, S.
Mitchell, C.D.
McKinney, P.A.
Birch, J.M.
Greaves, M.
Eden, T.
(2007). Childhood acute lymphoblastic leukemia and infections in the first year of life: A report from the United Kingdom Childhood Cancer Study. American journal of epidemiology,
Vol.165
(5),
pp. 496-9.
Greaves, M.
(2007). Darwinian medicine: a case for cancer. Nature reviews cancer,
Vol.7
(3),
pp. 213-9.
Greenman, C.
Stephens, P.
Smith, R.
Dalgliesh, G.L.
Hunter, C.
Bignell, G.
Davies, H.
Teague, J.
Butler, A.
Edkins, S.
O'Meara, S.
Vastrik, I.
Schmidt, E.E.
Avis, T.
Barthorpe, S.
Bhamra, G.
Buck, G.
Choudhury, B.
Clements, J.
Cole, J.
Dicks, E.
Forbes, S.
Gray, K.
Halliday, K.
Harrison, R.
Hills, K.
Hinton, J.
Jenkinson, A.
Jones, D.
Menzies, A.
Mironenko, T.
Perry, J.
Raine, K.
Richardson, D.
Shepherd, R.
Small, A.
Tofts, C.
Varian, J.
Webb, T.
West, S.
Widaa, S.
Yates, A.
Cahill, D.P.
Louis, D.N.
Goldstraw, P.
Nicholson, A.G.
Brasseur, F.
Looijenga, L.
Weber, B.L.
Chiew, Y.-.
deFazio, A.
Greaves, M.F.
Green, A.R.
Campbell, P.
Birney, E.
Easton, D.F.
Chenevix-Trench, G.
Tan, M.-.
Khoo, S.K.
Teh, B.T.
Yuen, S.T.
Leung, S.Y.
Wooster, R.
Futreal, P.A.
Stratton, M.R.
(2007). Patterns of somatic mutation in human cancer genomes. Nature,
Vol.446
(7132),
pp. 153-6.
full text
Greaves, M.
(2007). Godwits and blast crises: in memory of David Galton. Leuk lymphoma,
Vol.48
(12),
pp. 2280-2282.
Hughes, A.M.
Lightfoot, T.
Simpson, J.
Ansell, P.
McKinney, P.A.
Kinsey, S.E.
Mitchell, C.D.
Eden, T.O.
Greaves, M.
Roman, E.
(2007). Allergy and risk of childhood leukaemia: Results from the UKCCS. International journal of cancer,
Vol.121
(4),
pp. 819-6.
Bueno, C.
Montes, R.
García-Castro, J.
Greaves, M.
Menendez, P.
(2007). Human embryonic stem cells: A potential system for modeling infant leukemia harboring MLL-AF4 fusion gene. Drug discovery today: disease models,
Vol.4
(2),
pp. 53-60.
MacKenzie, J.
Greaves, M.F.
Eden, T.O.
Clayton, R.A.
Perry, J.
Wilson, K.S.
Jarrett, R.F.
(2006). The putative role of transforming viruses in childhood acute lymphoblastic leukemia. Haematologica-the hematology journal,
Vol.91
(2),
pp. 240-4.
Greaves, M.F.
(2006). Cord blood donor cell leukemia in recipients. Leukemia,
Vol.20
(9),
pp. 1633-3.
Eguchi, M.
Eguchi-Ishimae, M.
Knight, D.
Kearney, L.
Slany, R.
Greaves, M.
(2006). MLL chimeric protein activation renders cells vulnerable to chromosomal damage: An explanation for the very short latency of infant leukemia. Genes chromosomes & cancer,
Vol.45
(8),
pp. 754-7.
Greaves, M.
(2006). The causation of childhood leukemia: a paradox of progress?. Discov med,
Vol.6
(31),
pp. 24-28.
show abstract
Treatments, mostly combination chemotherapies, have been remarkably effective in managing many childhood leukemia cases. However, childhood leukemia is a heterogeneous (mixed) disease originating from different cell lineages and with distinct mechanisms. Authors described hypotheses of "population mixing" and "delayed infection" as causes of childhood leukemia..
Greaves, M.
(2006). Infection, immune responses and the aetiology of childhood leukaemia. Nat rev cancer,
Vol.6
(3),
pp. 193-203.
show abstract
Childhood leukaemia is the principal subtype of paediatric cancer and, despite success in treatment, its causes remain enigmatic. A plethora of candidate environmental exposures have been proposed, but most lack a biological rationale or consistent epidemiological evidence. Although there might not be a single or exclusive cause, an abnormal immune response to common infection(s) has emerged as a plausible aetiological mechanism..
Greaves, M.
So, C.W.
(2006). Alert and sniffy-nosed about MII-AF4?. Blood,
Vol.108
(2),
pp. 416-2.
Greaves, M.
(2005). In utero origins of childhood leukaemia. Early hum dev,
Vol.81
(1),
pp. 123-129.
show abstract
Chimaeric fusion genes derived by chromosome translocation are common molecular abnormalities in paediatric leukaemia and provide unique markers for the malignant clone. They have been especially informative in studies with twins concordant for leukaemia and in retrospective scrutiny of archived neonatal blood spots. These data have indicated that, in paediatric leukaemia, the majority of chromosome translocations arise in utero during foetal haemopoiesis. Chromosomal translocations and preleukaemic clones arise at a substantially higher frequency ( approximately 100x) before birth than the cumulative incidence or risk of disease, reflecting the requirement for complementary and secondary genetic events that occur postnatally. A consequence of the latter is a very variable and occasionally protracted postnatal latency of disease (1-15 years). These natural histories provide an important framework for consideration of key aetiological events in paediatric leukaemia..
Eguchi, M.
Eguchi-Ishimae, M.
Greaves, M.
(2005). Molecular pathogenesis of MLL-associated leukemias. International journal of hematology,
Vol.82
(1),
pp. 9-12.
Greaves, M.
(2005). How to win the Nobel prize: An unexpected life in science. Journal of the history of medicine and allied sciences,
Vol.60
(3),
pp. 383-3.
Gilham, C.
Peto, J.
Simpson, J.
Roman, E.
Eden, T.O.
Greaves, M.F.
Alexander, F.E.
(2005). Day care in infancy and risk of childhood acute lymphoblastic leukaemia: findings from UK case-control study. Bmj-british medical journal,
Vol.330
(7503),
pp. 1294-6.
Enver, T.
Tsuzuki, S.
Brown, J.
Hong, D.
Gupta, R.
Ford, T.
Egucchi, M.-.
Egucchi, M.
Greaves, M.
(2005). Developmental impact of leukemic fusion genes on stem cell fate. Ann n y acad sci,
Vol.1044,
pp. 16-23.
show abstract
Stem and progenitor cells present attractive targets for transformation by leukemia-associated fusion genes generated by chromosomal translocation. The mechanism by which these fusion genes corrupt the transcriptional programs of these cellular compartments remains largely unknown. We have sought to gain insight into these issues through expressing TEL-AML1 and TEL-TRKC fusion genes in murine stem cells and recording effects on cell behavior in a transplant setting..
Eguchi-Ishimae, M.
Eguchi, M.
Ishii, E.
Knight, D.
Sadakane, Y.
Isoyama, K.
Yabe, H.
Mizutani, S.
Greaves, M.
(2005). The association of a distinctive allele of NAD(P)H : quinone oxidoreductase with pediatric acute lymphoblastic leukemias with MLL fusion genes in Japan. Haematol-hematol j,
Vol.90
(11),
pp. 1511-1515.
show abstract
Background and Objectives. The enzyme NAD(P)H:quinone oxidoreductase (NQO1) detoxifies chemicals with quinone rings including benzene metabolites and flavonoids. Previous studies in Caucasian populations have provided evidence that a loss of function allele at nt 609 (C609T, Pro187Ser) is associated with increased risk of infant acute lymphoblastic leukemia (ALL) with MLL-AF4 fusion genes.Design and Methods. We genotyped 103 infants (<18 months) with ALL or acute myeloid leukemia (AML) in Japan and 185 controls for the frequency of allelic variation at nt 609 and 465 in NQO1 using standardized polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology.Results. The C609T polymorphism is very common in Japan but we found no link with altered risk for infant ALL. However, a variant of another allele at nt 465 (C465T, Arg139Trp), also associated with diminished enzyme activity, was strongly associated (OR 6.36; Cl 1.84-21.90; p = 0.002) with infant ALL, especially in t(4;11)(q21;q23), MLL-AF4. No association was found between this allele and risk of infant AML with MLL gene fusions or infant ALL without MLL gene fusions. The same C465T allele has been linked recently, in an Oriental population, to sensitivity to benzene hematotoxicity.Interpretation and Conclusions. These data endorse the notion that infant ALL with MLL fusion genes have a unique etiology possibly involving transplacental exposure to chemicals..
Feltbower, R.G.
Manda, S.O.
Gilthorpe, M.S.
Greaves, M.F.
Parslow, R.C.
Kinsey, S.E.
Bodansky, H.J.
McKinney, P.A.
(2005). Detecting small-area similarities in the epidemiology of childhood acute lymphoblastic leukemia and diabetes mellitus, type 1: A Bayesian approach. American journal of epidemiology,
Vol.161
(12),
pp. 1168-13.
Fischer, M.
Schwieger, M.
Horn, S.
Niebuhr, B.
Ford, A.
Roscher, S.
Bergholz, U.
Greaves, M.
Löhler, J.
Stocking, C.
(2005). Defining the oncogenic function of the TEL/AML1 (ETV6/RUNX1) fusion protein in a mouse model. Oncogene,
Vol.24
(51),
pp. 7579-13.
Eguchi, M.
Eguchi-Ishimae, M.
Green, A.
Enver, T.
Greaves, M.
(2005). Directing oncogenic fusion genes into stem cells via an SCL enhancer. Proc natl acad sci u s a,
Vol.102
(4),
pp. 1133-1138.
show abstract
full text
TEL-TRKC is a fusion gene generated by chromosomal translocation and encodes an activated tyrosine kinase. Uniquely, it is found in both solid tumors and leukemia. However, a single exon difference (in TEL) in TEL-TRKC fusions is associated with the two sets of cancer phenotypes. We expressed the two TEL-TRKC variants in vivo by using the 3' regulatory element of SCL that is selectively active in a subset of mesodermal cell lineages, including endothelial and hematopoietic stem cells and progenitors. The leukemia form of TEL-TRKC (-exon 5 of TEL) enhanced hematopoietic stem cell renewal and initiated leukemia. In contrast, the TEL-TRKC solid tumor variant (+ TEL exon 5) elicited an embryonic lethal phenotype with impairment of both angiogenesis and hematopoiesis indicative of an effect at the level of the hemangioblasts. The ability of TEL-TRKC to repress expression of Flk1, a critical regulator of early endothelial and hematopoietic cells, depended on TEL exon 5. These data indicate that related oncogenic fusion proteins similarly expressed in a hierarchy of early stem cells can have selective, cell type-specific developmental impacts..
Feltbower, R.G.
McKinney, P.A.
Greaves, M.F.
Parslow, R.C.
Bodansky, H.J.
(2004). International parallels in leukaemia and diabetes epidemiology. Archives of disease in childhood,
Vol.89
(1),
pp. 54-3.
Tsuzuki, S.
Seto, M.
Greaves, M.
Enver, T.
(2004). Modeling first-hit functions of the t(12;21) TEL-AML1 translocation in mice. Proceedings of the national academy of sciences of the united states of america,
Vol.101
(22),
pp. 8443-6.
full text
Maia, A.T.
Koechling, J.
Corbett, R.
Metzler, M.
Wiemels, J.L.
Greaves, M.
(2004). Protracted postnatal natural histories in childhood leukemia. Genes chromosomes & cancer,
Vol.39
(4),
pp. 335-6.
Maia, A.T.
Tussiwand, R.
Cazzaniga, G.
Rebulla, P.
Colman, S.
Biondi, A.
Greaves, M.
(2004). Identification of preleukemic precursors of hyperdiploid acute lymphoblastic leukemia in cord blood. Genes chromosomes & cancer,
Vol.40
(1),
pp. 38-6.
Gruszka-Westwood, A.M.
Horsley, S.W.
Martinez-Ramirez, A.
Harrison, C.J.
Kempski, H.
Moorman, A.V.
Ross, F.M.
Griffiths, M.
Greaves, M.F.
Kearney, L.
(2004). Comparative expressed sequence hybridisation studies of high-hyperdiploid childhood acute lymphoblastic leukemia. Genes chromosomes cancer,
Vol.41,
pp. 191-202.
Eguchi, M.
Eguchi-Ishimae, M.
Greaves, M.
(2004). The small oligomerization domain of gephyrin converts MLL to an oncogene. Blood,
Vol.103
(10),
pp. 3876-7.
Zelent, A.
Greaves, M.
Enver, T.
(2004). Role of the TEL-AML1 fusion gene in the molecular pathogenesis of childhood acute lymphoblastic leukaemia. Oncogene,
Vol.23
(24),
pp. 4275-4283.
show abstract
Balanced chromosomal translocations are frequently associated with haematopoietic neoplasms and often involve genes that encode transcription factors, which play critical roles in normal haematopoiesis. Fusion oncoproteins that arise from chimeric genes generated by such translocations are usually stable and consistent molecular markers for a given disease subtype and contribute to the leukaemogenic processes. The t(12;21)(p13;q22) chromosomal translocation is the most frequent illegitimate gene recombination in paediatric cancer, occurring in approximately 25% of common (c) B-cell precursor acute lymphoblastic leukaemia (cALL) cases. The rearrangement results in the in-frame fusion of the 5' region of the ETS-related gene, TEL (ETV6), to almost the entire AML1 (RUNX1) locus and is associated with favourable prognosis following conventional therapeutic strategies. We discuss here the prenatal origins of the TEL/AML1 translocation as an initiating mutation, the role of TEL-AML1 in cellular transformation and the molecular mechanisms by which the chimeric protein imposes altered patterns of gene expression..
Griffiths, G.J.
Koh, M.Y.
Brunton, V.G.
Cawthorne, C.
Reeves, N.A.
Greaves, M.
Tilby, M.J.
Pearson, D.G.
Ottley, C.J.
Workman, P.
Frame, M.C.
Dive, C.
(2004). Expression of kinase-defective mutants of c-Src in human metastatic colon cancer cells decreases Bcl-x(L) and increases oxaliplatin- and Fas-induced apoptosis. Journal of biological chemistry,
Vol.279
(44),
pp. 46113-9.
Greaves, M.F.
Maia, A.T.
Wiemels, J.L.
Ford, A.M.
(2003). Leukemia in twins: lessons in natural history. Blood,
Vol.102
(7),
pp. 2321-2333.
show abstract
Identical infant twins with concordant leukemia were first described in 1882, and since that time many such pairs of infants and older children have been described. It has long been recognized that this situation offers a unique opportunity to identify aspects of the developmental timing, natural history, and molecular genetics of pediatric leukemia in general. We reviewed both the older literature and more recent molecular biologic studies that have uncovered the basis of concordance of leukemia. Molecular markers of clonality, including unique, genomic fusion gene sequences, have provided unequivocal evidence that twin pairs of leukemia have a common clonal origin. The only plausible basis for this, first suggested more than 40 years ago, is that following initiation of leukemia in one twin fetus, clonal progeny spread to the co-twin via vascular anastomoses within a single, monochorionic placenta. This explanation has been endorsed by the identification of clonotypic gene fusion sequences in archived neonatal blood spots of individuals who subsequently developed leukemia. These analyses of twin leukemias have thrown considerable light on the natural history of disease. They reveal a frequent prenatal origin and an early or initiating role for chromosome translocations. Further, they provide evidence for a variable and often protracted latency and the need, in childhood acute lymphoblastic leukemia (ALL)/acute myeloblastic leukemia (AML), for further postnatal exposures and/or genetic events to produce clinical disease. We argue that these insights provide a very useful framework for attempts to understand etiologic mechanisms..
Zuna, J.
Muzikova, K.
Ford, A.M.
Maia, A.T.
Krejci, O.
Tousovska, K.
Oravkinova, I.
Greaves, M.
Trka, J.
(2003). Pre-natal, clonal origin of acute lymphoblastic leukaemia in triplets. Leukemia & lymphoma,
Vol.44
(12),
pp. 2099-4.
Petrie, K.
Guidez, F.
Howell, L.
Healy, L.
Waxman, S.
Greaves, M.
Zelent, A.
(2003). The histone deacetylase 9 gene encodes multiple protein isoforms. J biol chem,
Vol.278
(18),
pp. 16059-16072.
show abstract
Histone deacetylases (HDACs) perform an important function in transcriptional regulation by modifying the core histones of the nucleosome. We have now fully characterized a new member of the Class II HDAC family, HDAC9. The enzyme contains a conserved deacetylase domain, represses reporter activity when recruited to a promoter, and utilizes histones H3 and H4 as substrates in vitro and in vivo. HDAC9 is expressed in a tissue-specific pattern that partially overlaps that of HDAC4. Within the human hematopoietic system, expression of HDAC9 is biased toward cells of monocytic and lymphoid lineages. The HDAC9 gene encodes multiple protein isoforms, some of which display distinct cellular localization patterns. For example, full-length HDAC9 is localized in the nucleus, but the isoform lacking the region encoded by exon 7 is in the cytoplasm. HDAC9 interacts and co-localizes in vivo with a number of transcriptional repressors and co-repressors, including TEL and N-CoR, whose functions have been implicated in the pathogenesis of hematological malignancies. These results suggest that HDAC9 plays a role in hematopoiesis; its deregulated expression may be associated with some human cancers..
Greaves, M.F.
Wiemels, J.
(2003). Origins of chromosome translocations in childhood leukaemia. Nat rev cancer,
Vol.3
(9),
pp. 639-649.
show abstract
Chromosome translocations are often early or initiating events in leukaemogenesis, occurring prenatally in most cases of childhood leukaemia. Although these genetic changes are necessary, they are usually not sufficient to cause leukaemia. How, when and where do translocations arise? And can these insights aid our understanding of the natural history, pathogenesis and causes of leukaemia?.
Greaves, M.
(2003). Pre-natal origins of childhood leukemia. Rev clin exp hematol,
Vol.7
(3),
pp. 233-245.
show abstract
Chimeric fusion genes derived by chromosome translocation provide stable, sensitive and clone-specific markers for tracking the origins of leukemic cells and the natural history of disease and have been particularly informative in studies with twins concordant for leukemia and in retrospective scrutiny of archived neonatal blood spots. These data have indicated that in pediatric leukemia the majority, but not all, of the chromosome translocations arise, in utero, during fetal hemopoiesis, probably as initiating events. In most cases, functionally complementary and secondary genetic events are also required. These are acquired rapidly, and possibly in utero also, in infant acute lymphoblastic leukemia (ALL) but post-natally for most childhood ALL and acute myeloblastic leukemia (AML). An important consequence of the latter is a very variable and occasionally protracted post-natal latency (1-15 years). Another important corollary is that functional chromosomal translocations and pre-leukemic clones arise at a substantially higher frequency (approximately 100x) before birth than the cumulative incidence or risk of disease. These natural histories provide an important framework for consideration of key etiological events in pediatric leukemia..
Maia, A.T.
van der Velden, V.H.
Harrison, C.J.
Szczepanski, T.
Williams, M.D.
Griffiths, M.J.
van Dongen, J.J.
Greaves, M.F.
(2003). Prenatal origin of hyperdiploid acute lymphoblastic leukemia in identical twins. Leukemia,
Vol.17
(11),
pp. 2202-5.
Eguchi, M.
Eguchi-Ishimae, M.
Greaves, M.
(2003). The role of the MLL gene in infant leukemia. International journal of hematology,
Vol.78
(5),
pp. 390-12.
Chan, L.C.
Lam, T.H.
Li, C.K.
Lau, Y.L.
Li, C.K.
Yuen, H.L.
Lee, C.W.
Ha, S.Y.
Yuen, P.M.
Leung, N.K.
Patheal, S.L.
Greaves, M.F.
Alexander, F.E.
(2002). Is the timing of exposure to infection a major determinant of acute lymphoblastic leukaemia in Hong Kong?. Paediatric and perinatal epidemiology,
Vol.16
(2),
pp. 154-12.
Greaves, M.
(2002). Cancer causation: the Darwinian downside of past success?. Lancet oncology,
Vol.3
(4),
pp. 244-8.
Taylor, G.M.
Dearden, S.
Ravetto, P.
Ayres, M.
Watson, P.
Hussain, A.
Greaves, M.F.
Alexander, F.
Eden, O.B.
UKCCS Investigators,
(2002). Genetic susceptibility to childhood common acute lymphoblastic leukaemia is associated with polymorphic peptide-binding pocket profiles in HLA-DPB1*0201. Hu mol genet,
Vol.11,
pp. 1585-1597.
Greaves, M.
(2002). Cystic Fibrosis heterozygosity: Darwinian bet on cancer protection? Author's reply. Lancet oncology,
Vol.3
(7),
pp. 396-1.
Greaves, M.
(2002). Childhood leukaemia. Bmj,
Vol.324
(7332),
pp. 283-287.
full text
Mori, H.
Colman, S.M.
Xiao, Z.
Ford, A.M.
Healy, L.E.
Donaldson, C.
Hows, J.M.
Navarrete, C.
Greaves, M.
(2002). Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc natl acad sci u s a,
Vol.99
(12),
pp. 8242-8247.
show abstract
full text
Studies on monozygotic twins with concordant leukemia and retrospective scrutiny of neonatal blood spots of patients with leukemia indicate that chromosomal translocations characteristic of pediatric leukemia often arise prenatally, probably as initiating events. The modest concordance rate for leukemia in identical twins ( approximately 5%), protracted latency, and transgenic modeling all suggest that additional postnatal exposure and/or genetic events are required for clinically overt leukemia development. This notion leads to the prediction that chromosome translocations, functional fusion genes, and preleukemic clones should be present in the blood of healthy newborns at a rate that is significantly greater than the cumulative risk of the corresponding leukemia. Using parallel reverse transcriptase-PCR and real-time PCR (Taqman) screening, we find that the common leukemia fusion genes, TEL-AML1 or AML1-ETO, are present in cord bloods at a frequency that is 100-fold greater than the risk of the corresponding leukemia. Single-cell analysis by cell enrichment and immunophenotype/fluorescence in situ hybridization multicolor staining confirmed the presence of translocations in restricted cell types corresponding to the B lymphoid or myeloid lineage of the leukemias that normally harbor these fusion genes. The frequency of positive cells (10(-4) to 10(-3)) indicates substantial clonal expansion of a progenitor population. These data have significant implications for the pathogenesis, natural history, and etiology of childhood leukemia..
Wiemels, J.L.
Xiao, Z.
Buffler, P.A.
Maia, A.T.
Ma, X.
Dicks, B.M.
Smith, M.T.
Zhang, L.
Feusner, J.
Wiencke, J.
Pritchard-Jones, K.
Kempski, H.
Greaves, M.
(2002). In utero origin of t(8;21) AML1-ETO translocations in childhood acute myeloid leukemia. Blood,
Vol.99
(10),
pp. 3801-3805.
show abstract
Recent reports have established the prenatal origin of leukemia translocations and resultant fusion genes in some patients, including MLL-AF4 translocations in infants and TEL-AML1 translocations in children. We now report evidence for the prenatal origin of a translocation in childhood acute myeloid leukemia (AML). The t(8;21) AML1-ETO translocations were sequenced at the genomic level in 10 diagnostic leukemia samples from children with available neonatal Guthrie blood spots. Clonotypic genomic AML1-ETO sequences were detected in the Guthrie spots for 5 individuals, providing unambiguous evidence of prenatal origin in these cases. Two of these patients were older than 10 years of age at diagnosis, indicative of a protracted postnatal latency. Three of the patients were assessed for the persistence of genomic fusion sequences in complete clinical remission samples and were found to be positive. These data indicate that t(8;21) in childhood AML can arise in utero, possibly as an initiating event in childhood AML, and may establish a long-lived or stable parental clone that requires additional secondary genetic alterations to cause leukemia..
Ford, A.M.
Fasching, K.
Panzer-Grümayer, E.R.
Koenig, M.
Haas, O.A.
Greaves, M.F.
(2001). Origins of "late" relapse in childhood acute lymphoblastic leukemia with TEL-AML1 fusion genes. Blood,
Vol.98
(3),
pp. 558-564.
show abstract
Approximately 20% of childhood B-precursor acute lymphoblastic leukemia (ALL) has a TEL-AML1 fusion gene, often in association with deletions of the nonrearranged TEL allele. TEL-AML1 gene fusion appears to be an initiating event and usually occurs before birth, in utero. This subgroup of ALL generally presents with low- or medium-risk features and overall has a very good prognosis. Some patients, however, do have relapses late or after the cessation of treatment, at least on some therapeutic protocols. They usually achieve sustained second remissions. Posttreatment relapses, or even very late relapses (5-20 years after diagnosis), in childhood ALL are clonally related to the leukemic cells at diagnosis (by IGH or T-cell receptor [TCR] gene sequencing) and are considered, therefore, to represent a slow re-emergence or escape of the initial clone seen at diagnosis. Microsatellite markers and fluorescence in situ hybridization identified deletions of the unrearranged TEL allele and IGH/TCR gene rearrangements were analyzed; the results show that posttreatment relapse cells in 2 patients with TEL-AML1-positive ALL were not derived from the dominant clone present at diagnosis but were from a sibling clone. In contrast, a patient who had a relapse while on treatment with TEL-AML1 fusion had essentially the same TEL deletion, though with evidence for microsatellite instability 5(') of TEL gene deletion at diagnosis, leading to extended 5(') deletion at relapse. It is speculated that, in some patients, combination chemotherapy for childhood ALL may fail to eliminate a fetal preleukemic clone with TEL-AML1 and that a second, independent transformation event within this clone after treatment gives rise to a new leukemia masquerading as relapse. (Blood. 2001;98:558-564).
MacKenzie, J.
Gallagher, A.
Clayton, R.A.
Perry, J.
Eden, O.B.
Ford, A.M.
Greaves, M.F.
Jarrett, R.F.
(2001). Screening for herpesvirus genomes in common acute lymphoblastic leukemia. Leukemia,
Vol.15
(3),
pp. 415-7.
Xiao, Z.
Greaves, M.F.
Buffler, P.
Smith, M.T.
Segal, M.R.
Dicks, B.M.
Wiencke, J.K.
Wiemels, J.L.
(2001). Molecular characterization of genomic AML1-ETO fusions in childhood leukemia. Leukemia,
Vol.15
(12),
pp. 1906-8.
Eguchi, M.
Eguchi-Ishimae, M.
Seto, M.
Morishita, K.
Suzuki, K.
Ueda, R.
Ueda, K.
Kamada, N.
Greaves, M.
(2001). GPHN, a novel partner gene fused to MLL in a leukemia with t(11;14)(q23;q24). Genes chromosomes & cancer,
Vol.32
(3),
pp. 212-10.
Greaves, M.
(2001). Biological and clinical impact of chromosomal translocations in childhood leukaemia. British journal of cancer,
Vol.85,
pp. 11-1.
Cabrera, M.E.
Campbell, M.
Quintana, J.
Undurraga, M.S.
Ford, A.A.
Greaves, M.F.
(2001). [Clinical significance and frequency of the 11q23/MLL genetic molecular alteration in Chilean infants with acute leukemia]. Rev med chil,
Vol.129
(6),
pp. 634-642.
show abstract
BACKGROUND: Acute leukemia (AL) in infants generally shows distinctive biologic features and has a poor prognosis. AIM: To study the frequency of the cytogenetic alteration of 11q23 chromosome or the recombination of MLL gene in infants less than 18 months old, with acute leukemia. PATIENTS AND METHODS: We analyzed 37 cases of AL in infants less than 18 months of age diagnosed in Chile from 1989 to 1999. The clinical features and cytogenetic/molecular defects of 11q23MLL gene rearrangement and their influence in prognosis were determined. RESULTS: There were 18 cases of acute Lymphoblastic leukemia (ALL) characterized by female sex (67%) high presenting leukocyte count (median 99 x 109/L), blast cells with a CD10 negative phenotype (50%) and 11q23/MLL rearrangement (39%). Molecular abnormalities of 11q23 were significantly associated with adverse prognosis, with an event free survival (EFS) of only 14 +/- 12%. Interestingly, infants with germ line 11q23 had a very good outcome with an EFS of 73 +/- 11% (p < 0.025). There were 19 cases of acute myeloblastic leukemia (AML) characterized by male sex (63%) high leukocyte count (median 93 x 109/L), FAB-MS morphology (53%) and 11q23/MLL rearrangement (53%). EFS was very poor, 20 +/- 9% and 33 +/- 4% for rearranged and germinal group respectively (p = NS), due to a high mortality rate during the first month of diagnosis. CONCLUSIONS: These findings demonstrate that Chilean ALL infants with 11q23 abnormalities have a very poor prognosis. However those with germinal state can enjoy a prolonged disease free survival with the current treatment protocols..
Greaves, M.F.
(2001). Commentary: Birth order and risk of childhood acute lymphoblastic leukaemia (ALL). Int j epidemiol,
Vol.30
(6),
pp. 1438-1439.
Alexander, F.E.
Patheal, S.L.
Biondi, A.
Brandalise, S.
Cabrera, M.E.
Chan, L.C.
Chen, Z.
Cimino, G.
Cordoba, J.C.
Gu, L.J.
Hussein, H.
Ishii, E.
Kamel, A.M.
Labra, S.
Magalhaes, I.Q.
Mizutani, S.
Petridou, E.
de Oliveira, M.P.
Yuen, P.
Wiemels, J.L.
Greaves, M.F.
(2001). Transplacental chemical exposure and risk of infant leukemia with MLL gene fusion. Cancer research,
Vol.61
(6),
pp. 2542-5.
Maia, A.T.
Ford, A.M.
Jalali, G.R.
Harrison, C.J.
Taylor, G.M.
Eden, O.B.
Greaves, M.F.
(2001). Molecular tracking of leukemogenesis in a triplet pregnancy. Blood,
Vol.98
(2),
pp. 478-5.
Jalali, G.R.
Martineau, M.
Greaves, M.F.
Harrison, C.J.
(2001). Loss of chromosomal integrity prior to ETV6/AML1 fusion?. Blood,
Vol.98
(11),
pp. 188B-2.
Wiemels, J.L.
Smith, R.N.
Taylor, G.M.
Eden, O.B.
Alexander, F.E.
Greaves, M.F.
United Kingdom Childhood Cancer Study investigators,
(2001). Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia. Proc natl acad sci u s a,
Vol.98
(7),
pp. 4004-4009.
show abstract
full text
Low folate intake as well as alterations in folate metabolism as a result of polymorphisms in the enzyme methylenetetrahydrofolate reductase (MTHFR) have been associated with an increased incidence of neural tube defects, vascular disease, and some cancers. Polymorphic variants of MTHFR lead to enhanced thymidine pools and better quality DNA synthesis that could afford some protection from the development of leukemias, particularly those with translocations. We now report associations of MTHFR polymorphisms in three subgroups of pediatric leukemias: infant lymphoblastic or myeloblastic leukemias with MLL rearrangements and childhood lymphoblastic leukemias with either TEL-AML1 fusions or hyperdiploid karyotypes. Pediatric leukemia patients (n = 253 total) and healthy newborn controls (n = 200) were genotyped for MTHFR polymorphisms at nucleotides 677 (C-->T) and 1,298 (A-->C). A significant association for carriers of C677T was demonstrated for leukemias with MLL translocations (MLL+, n = 37) when compared with controls [adjusted odd ratios (OR) = 0.36 with a 95% confidence interval (CI) of 0.15-0.85; P = 0.017]. This protective effect was not evident for A1298C alleles (OR = 1.14). In contrast, associations for A1298C homozygotes (CC; OR = 0.26 with a 95% CI of 0.07--0.81) and C677T homozygotes (TT; OR = 0.49 with a 95% CI of 0.20--1.17) were observed for hyperdiploid leukemias (n = 138). No significant associations were evident for either polymorphism with TEL-AML1+ leukemias (n = 78). These differences in allelic associations may point to discrete attributes of the two alleles in their ability to alter folate and one-carbon metabolite pools and impact after DNA synthesis and methylation pathways, but should be viewed cautiously pending larger follow-up studies. The data provide evidence that molecularly defined subgroups of pediatric leukemias have different etiologies and also suggest a role of folate in the development of childhood leukemia..
Magalhaes, I.Q.
Pombo-de-Oliveira, M.S.
Bennett, C.A.
Cordoba, J.C.
Dobbin, J.
Ford, A.M.
Greaves, M.F.
(2000). TEL-AML1 fusion gene frequency in paediatric acute lymphoblastic leukaemia in Brazil. British journal of haematology,
Vol.111
(1),
pp. 204-4.
Guidez, F.
Petrie, K.
Ford, A.M.
Lu, H.F.
Bennett, C.A.
MacGregor, A.
Hannemann, J.
Ito, Y.
Ghysdael, J.
Greaves, M.
Wiedemann, L.M.
Zelent, A.
(2000). Recruitment of the nuclear receptor corepressor N-CoR by the TEL moiety of the childhood leukemia-associated TEL-AML1 oncoprotein. Blood,
Vol.96
(7),
pp. 2557-5.
Wiemels, J.L.
Alexander, F.E.
Cazzaniga, G.
Biondi, A.
Mayer, S.P.
Greaves, M.
(2000). Microclustering of TEL-AML1 translocation breakpoints in childhood acute lymphoblastic leukemia. Genes chromosomes & cancer,
Vol.29
(3),
pp. 219-10.
Greaves, M.F.
(2000). Evolution, immune response, and cancer. Lancet,
Vol.356
(9234),
pp. 1034-1.
Mori, H.
Xiao, Z.
Ford, A.M.
Healy, L.E.
Donaldson, C.
Hows, J.M.
Navarrete, C.
Greaves, M.F.
(2000). TEL-AML1 and AML1-ETO fusion sequences in normal newborn cord bloods. Blood,
Vol.96
(11),
pp. 88A-1.
Ford, A.M.
Fasching, K.
Panzer-Grumayer, E.R.
Koenig, M.
Haas, O.A.
Greaves, M.F.
(2000). Origins of 'late' relapse in childhood acute lymphoblastic leukaemia with TEL-AML1 fusion genes. Blood,
Vol.96
(11),
pp. 464A-1.
Maia, A.T.
Ford, A.M.
Martineau, M.
Harrison, C.J.
Taylor, G.M.
Eden, O.B.
Greaves, M.F.
(2000). Molecular tracking of leukaemogenesis: Insights from a triplet pregnancy. Blood,
Vol.96
(11),
pp. 542A-1.
Wiemels, J.L.
Smith, R.N.
Taylor, G.M.
Eden, O.B.
Alexander, F.E.
Greaves, M.F.
(2000). Methylene tetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia. Blood,
Vol.96
(11),
pp. 541A-1.
Xiao, Z.J.
Greaves, M.F.
Buffler, P.
Smith, M.T.
Segal, M.
Dicks, B.M.
Wiencke, J.K.
Wiemels, J.L.
(2000). Genomic structure of t(8;21) (AML1-ETO) translocation fusions in childhood acute myeloid leukemia indicate etiologic clues to breakpoint formation. Blood,
Vol.96
(11),
pp. 691A-1.
Greaves, M.F.
Ford, A.M.
Wiemels, J.L.
(2000). Prenatal diagnosis of acute lymphoblastic leukaemia - Reply. Lancet,
Vol.355
(9208),
pp. 1017-1.
Greaves, M.F.
(2000). Disease should be targeted from all angles. Nature,
Vol.407
(6807),
pp. 941-1.
Kim-Rouille, M.H.
MacGregor, A.
Wiedemann, L.M.
Greaves, M.F.
Navarrete, C.
(1999). MLL-AF4 gene fusions in normal newborns. Blood,
Vol.93
(3),
pp. 1107-2.
Gibbons, D.L.
MacDonald, D.
McCarthy, K.P.
Cleary, H.J.
Plumb, M.
Wright, E.G.
Greaves, M.F.
(1999). An E mu-BCL-2 transgene facilitates leukaemogenesis by ionizing radiation. Oncogene,
Vol.18
(26),
pp. 3870-8.
Cabrera, M.E.
Labra, S.
Meneses, P.
Matutes, E.
Cartier, L.
Ford, A.M.
Greaves, M.F.
(1999). Adult T cell leukemia lymphoma in Chile A clinico pathological and molecular study of 26 patients. Revista medica de chile,
Vol.127
(8),
pp. 935-10.
MacKenzie, J.
Perry, J.
Ford, A.M.
Jarrett, R.F.
Greaves, M.
(1999). JC and BK virus sequences are not detectable in leukaemic samples from children with common acute lymphoblastic leukaemia. British journal of cancer,
Vol.81
(5),
pp. 898-2.
Greaves, M.
(1999). Molecular genetics, natural history and the demise of childhood leukaemia (Reprinted from Eur J Cancer, vol 35, pg 173-185, 1999). European journal of cancer,
Vol.35
(14),
pp. 1941-13.
Greaves, M.
(1999). Molecular genetics, natural history and the demise of childhood leukaemia. European journal of cancer,
Vol.35
(2),
pp. 173-13.
Alexander, F.
Greaves, M.
(1999). Inaccuracy and vested interests - two threats to etiologic research - Reply. Leukemia,
Vol.13
(3),
pp. 496-2.
Wiemels, J.L.
Pagnamenta, A.
Taylor, G.M.
Eden, O.B.
Alexander, F.E.
Greaves, M.F.
(1999). A lack of a functional NAD(P)H : quinone oxidoreductase allele is selectively associated with pediatric leukemias that have MLL fusions. Cancer research,
Vol.59
(16),
pp. 4095-5.
Wiemels, J.L.
Greaves, M.
(1999). Structure and possible mechanisms of TEL-AML1 gene fusions in childhood acute lymphoblastic leukemia. Cancer research,
Vol.59
(16),
pp. 4075-8.
Wiemels, J.L.
Cazzaniga, G.
Daniotti, M.
Eden, O.B.
Addison, G.M.
Masera, G.
Saha, V.
Biondi, A.
Greaves, M.F.
(1999). Prenatal origin of acute lymphoblastic leukaemia in children. Lancet,
Vol.354
(9189),
pp. 1499-5.
Nishii, K.
Gibbons, D.L.
Titley, I.
Papworth, D.
Goodhead, D.T.
Greaves, M.
(1998). Regulation of the apoptotic response to radiation damage in B cell development. Cell death and differentiation,
Vol.5
(1),
pp. 77-10.
Enver, T.
Greaves, M.
(1998). Loops, lineage, and leukemia. Cell,
Vol.94
(1),
pp. 9-4.
Ford, A.M.
Bennett, C.A.
Price, C.M.
Bruin, M.C.
Van Wering, E.R.
Greaves, M.
(1998). Fetal origins of the TEL-AML1 fusion gene in identical twins with leukemia. Proc natl acad sci u s a,
Vol.95
(8),
pp. 4584-4588.
show abstract
full text
The TEL (ETV6)-AML1 (CBFA2) gene fusion is the most common reciprocal chromosomal rearrangement in childhood cancer occurring in approximately 25% of the most predominant subtype of leukemia- common acute lymphoblastic leukemia. The TEL-AML1 genomic sequence has been characterized in a pair of monozygotic twins diagnosed at ages 3 years, 6 months and 4 years, 10 months with common acute lymphoblastic leukemia. The twin leukemic DNA shared the same unique (or clonotypic) but nonconstitutive TEL-AML1 fusion sequence. The most plausible explanation for this finding is a single cell origin of the TEL-AML fusion in one fetus in utero, probably as a leukemia-initiating mutation, followed by intraplacental metastasis of clonal progeny to the other twin. Clonal identity is further supported by the finding that the leukemic cells in the two twins shared an identical rearranged IGH allele. These data have implications for the etiology and natural history of childhood leukemia..
Greaves, M.F.
(1997). Aetiology of acute leukaemia. Lancet,
Vol.349
(9048),
pp. 344-6.
Ford, A.M.
PombodeOliveira, M.S.
McCarthy, K.P.
MacLean, J.M.
Carrico, K.C.
Vincent, R.F.
Greaves, M.
(1997). Monoclonal origin of concordant T-cell malignancy in identical twins. Blood,
Vol.89
(1),
pp. 281-5.
Greaves, M.
(1997). Differentiation decisions and their corruption in leukaemia. Leukemia,
Vol.11
(6),
pp. 898-4.
Griffiths, S.D.
Clarke, A.R.
Healy, L.E.
Ross, G.
Ford, A.M.
Hooper, M.L.
Wyllie, A.H.
Greaves, M.
(1997). Absence of p53 permits propagation of mutant cells following genotoxic damage. Oncogene,
Vol.14
(5),
pp. 523-9.
Gale, K.B.
Ford, A.M.
Repp, R.
Borkhardt, A.
Keller, C.
Eden, O.B.
Greaves, M.F.
(1997). Backtracking leukemia to birth: identification of clonotypic gene fusion sequences in neonatal blood spots. Proc natl acad sci u s a,
Vol.94
(25),
pp. 13950-13954.
show abstract
full text
Epidemiological evidence has suggested that some pediatric leukemias may be initiated in utero and, for some pairs of identical twins with concordant leukemia, this possibility has been strongly endorsed by molecular studies of clonality. Direct evidence for a prenatal origin can only be derived by prospective or retrospective detection of leukemia-specific molecular abnormalities in fetal or newborn samples. We report a PCR-based method that has been developed to scrutinize neonatal blood spots (Guthrie cards) for the presence of numerically infrequent leukemic cells at birth in individuals who subsequently developed leukemia. We demonstrate that unique or clonotypic MLL-AF4 genomic fusion sequences are present and detectable in neonatal blood spots from individuals who were diagnosed with acute lymphoblastic leukemia at ages 5 months to 2 years and, therefore, have arisen during fetal hematopoiesis in utero. This result provides unequivocal evidence for a prenatal initiation of acute leukemia in young patients. The method should be applicable to other fusion genes in children with common subtypes of leukemia and will be of value in attempts to unravel the natural history and etiology of this major subtype of pediatric cancer..
Cimino, G.
Rapanotti, M.C.
Biondi, A.
Elia, L.
LoCoco, F.
Price, C.
Rossi, V.
Rivolta, A.
Canaani, E.
Croce, C.M.
Mandelli, F.
Greaves, M.
(1997). Infant acute leukemias show the same biased distribution of ALL1 gene breaks as topoisomerase II related secondary acute leukemias. Cancer research,
Vol.57
(14),
pp. 2879-5.
Hu, M.
Krause, D.
Greaves, M.
Sharkis, S.
Dexter, M.
Heyworth, C.
Enver, T.
(1997). Multilineage gene expression precedes commitment in the hemopoietic system. Genes & development,
Vol.11
(6),
pp. 774-12.
Greaves, M.
(1997). Silence of the leukemic clone. New england journal of medicine,
Vol.336
(5),
pp. 367-3.
Alexander, F.E.
Chan, L.C.
Lam, T.H.
Yuen, P.
Leung, N.K.
Ha, S.Y.
Yuen, H.L.
Li, C.K.
Lau, Y.L.
Greaves, M.F.
(1997). Clustering of childhood leukaemia in Hong Kong: Association with the childhood peak and common acute lymphoblastic leukaemia and with population mixing. British journal of cancer,
Vol.75
(3),
pp. 457-7.
Cabrera, M.E.
Labra, S.
Ugarte, S.
Matutes, E.
Greaves, M.F.
(1996). Immunophenotypic, clinical and laboratory features of 500 children and 131 adults with acute lymphoblastic leukemia. Revista medica de chile,
Vol.124
(3),
pp. 293-7.
Greaves, M.F.
(1996). Infant leukaemia biology, aetiology and treatment. Leukemia,
Vol.10
(2),
pp. 372-6.
Ford, A.M.
Bennett, C.A.
Healy, L.E.
Towatari, M.
Greaves, M.F.
Enver, T.
(1996). Regulation of the myeloperoxidase enhancer binding proteins Pu1, C-EBP alpha, -beta, and -delta during granulocyte-lineage specification. Proceedings of the national academy of sciences of the united states of america,
Vol.93
(20),
pp. 10838-6.
full text
Campbell, M.
Cabrera, M.E.
Legues, M.E.
Ridge, S.
Greaves, M.
(1996). Discordant clinical presentation and outcome in infant twins sharing a common clonal leukaemia. British journal of haematology,
Vol.93
(1),
pp. 166-4.
Greaves, M.
(1996). Is telomerase activity in cancer due to selection of stem cells and differentiation arrest?. Trends in genetics,
Vol.12
(4),
pp. 127-2.
Nishii, K.
Kabarowski, J.H.
Gibbons, D.L.
Griffiths, S.D.
Titley, I.
Wiedemann, L.M.
Greaves, M.F.
(1996). ts BCR-ABL kinase activation confers increased resistance to genotoxic damage via cell cycle block. Oncogene,
Vol.13
(10),
pp. 2225-10.
GREAVES, M.F.
(1995). REQUEST FOR LEUKEMIC SAMPLES FROM TWINS. Leukemia,
Vol.9
(2),
pp. 362-2.
MAHMOUD, H.H.
RIDGE, S.A.
BEHM, F.G.
PUI, C.H.
FORD, A.M.
RAIMONDI, S.C.
GREAVES, M.F.
(1995). INTRAUTERINE MONOCLONAL ORIGIN OF NEONATAL CONCORDANT ACUTE LYMPHOBLASTIC-LEUKEMIA IN MONOZYGOTIC TWINS. Medical and pediatric oncology,
Vol.24
(2),
pp. 77-5.
Ridge, S.A.
Cabrera, M.E.
Ford, A.M.
Tapia, S.
Risueno, C.
Labra, S.
Barriga, F.
Greaves, M.F.
(1995). Rapid intraclonal switch of lineage dominance in congenital leukaemia with a MLL gene rearrangement. Leukemia,
Vol.9
(12),
pp. 2023-4.
Cartier, L.
Castillo, J.L.
Cabrera, M.E.
Araya, F.
Matutes, E.
Ford, A.M.
Greaves, M.F.
(1995). HTLV-I positive progressive spastic paraparesis (TSP) associated with a lymphoid disorder in three Chilean patients. Leuk lymphoma,
Vol.17
(5-6),
pp. 459-464.
show abstract
We describe the clinical and laboratory features in three Caucasian Chilean patients with tropical spastic paraparesis (TSP) associated with/or preceded by a lymphoproliferative disorder involving cutaneous lesions and localised lymphadenopathy. The neurological symptoms and signs were characteristic of TSP and CSF examination revealed the presence of oligoclonal bands. All three patients had a moderate leucocytosis (10-14 x 10(9)/l) with eosinophilia and a minority (2-4%) of circulating atypical polylobed or ATLL-like lymphocytes. Lymph node histology showed a diffuse pattern of infiltration (1 case) and marked expansion of the paracortical zone with convoluted lymphocytes and immunoblasts (2 cases). Skin biopsy demonstrated a dermal lymphoid infiltration with epidermotropism. Antibodies to HTLV-I were detected in the serum and CSF in the three patients and Southern blot analysis of peripheral blood mononuclear cells showed a monoclonal integration of HTLV-I proviral DNA in one case whereas in the two others the pattern was indicative of low level polyclonal integration. All three patients were treated with prednisolone and one with PUVA with transient partial response on the skin and neurological manifestations. Two patients died months to 5 years from presentation and the other is alive 12 years from diagnosis with active neurological and skin disease. The simultaneous occurrence of HTLV-I associated TSP with smouldering ATLL and a cutaneous ATLL or pre-leukaemic form is discussed..
Healy, L.
May, G.
Gale, K.
Grosveld, F.
Greaves, M.
Enver, T.
(1995). The stem cell antigen CD34 functions as a regulator of hemopoietic cell adhesion. Proceedings of the national academy of sciences of the united states of america,
Vol.92
(26),
pp. 12240-5.
full text
MATAMOROS, N.
MATUTES, E.
HERNANDEZ, M.
GALMES, A.
PEREZPAYAROLS, J.
BUCCHERI, V.
MORILLA, R.
CATOVSKY, D.
HEALY, L.E.
RIDGE, S.A.
GREAVES, M.F.
(1994). NEONATAL MIXED LINEAGE ACUTE-LEUKEMIA. Leukemia,
Vol.8
(7),
pp. 1236-7.
ZHU, J.D.
BENNETT, C.A.
MACGREGOR, A.D.
GREAVES, M.F.
GOODWIN, G.H.
FORD, A.M.
(1994). A MYELOID-LINEAGE-SPECIFIC ENHANCER UPSTREAM OF THE MOUSE MYELOPEROXIDASE (MPO) GENE. Leukemia,
Vol.8
(5),
pp. 717-7.
RIDGE, S.A.
DYER, M.
GREAVES, M.F.
WIEDEMANN, L.M.
(1994). LACK OF MDM2 AMPLIFICATION IN HUMAN LEUKEMIA. British journal of haematology,
Vol.86
(2),
pp. 407-3.
CABRERA, M.E.
LABRA, S.
CATOVSKY, D.
FORD, A.M.
COLMAN, S.M.
GREAVES, M.F.
MATUTES, E.
(1994). HTLV-I POSITIVE ADULT T-CELL LEUKAEMIA/LYMPHOMA (ATLL) IN CHILE. Leukemia,
Vol.8
(10),
pp. 1763-5.
GREAVES, M.F.
ALEXANDER, F.E.
(1994). EPIDEMIOLOGIC CHARACTERISTICS OF CHILDHOOD ACUTE LYMPHOCYTIC-LEUKEMIA. Leukemia,
Vol.8
(10),
pp. 1793-2.
GRIFFITHS, S.D.
GOODHEAD, D.T.
MARSDEN, S.J.
WRIGHT, E.G.
KRAJEWSKI, S.
REED, J.C.
KORSMEYER, S.J.
GREAVES, M.
(1994). INTERLEUKIN 7-DEPENDENT B-LYMPHOCYTE PRECURSOR CELLS ARE ULTRASENSITIVE TO APOPTOSIS. Journal of experimental medicine,
Vol.179
(6),
pp. 1789-9.
CABRERA, M.E.
LABRA, S.
GREAVES, M.F.
FORD, A.H.
MATUTES, E.
CATOVSKY, D.
(1994). HTLV-I POSITIVE ADULT T-CELL LEUKEMIA-LYMPHOMA (ATLL) IN CHILE. Aids research and human retroviruses,
Vol.10
(4),
pp. 477-1.
GRIFFITHS, S.D.
MARSDEN, S.J.
WRIGHT, E.G.
GREAVES, M.F.
GOODHEAD, D.T.
(1994). LETHALITY AND MUTAGENESIS OF B-LYMPHOCYTE PROGENITOR CELLS FOLLOWING EXPOSURE TO ALPHA-PARTICLES AND X-RAYS. International journal of radiation biology,
Vol.66
(2),
pp. 197-9.
GREAVES, M.F.
(1993). STEM-CELL ORIGINS OF LEUKEMIA AND CURABILITY. British journal of cancer,
Vol.67
(3),
pp. 413-11.
BUNCE, C.M.
FRENCH, P.J.
ALLEN, P.
MOUNTFORD, J.C.
MOOR, B.
GREAVES, M.F.
MICHELL, R.H.
BROWN, G.
(1993). COMPARISON OF THE LEVELS OF INOSITOL METABOLITES IN TRANSFORMED HEMATOPOIETIC-CELLS AND THEIR NORMAL COUNTERPARTS. Biochemical journal,
Vol.289,
pp. 667-7.
GREAVES, M.F.
COLMAN, S.M.
BEARD, M.E.
BRADSTOCK, K.
CABRERA, M.E.
CHEN, P.M.
JACOBS, P.
LAMPOTANG, P.R.
MACDOUGALL, L.G.
WILLIAMS, C.K.
ALEXANDER, F.E.
(1993). GEOGRAPHICAL-DISTRIBUTION OF ACUTE LYMPHOBLASTIC-LEUKEMIA SUBTYPES - 2ND REPORT OF THE COLLABORATIVE GROUP-STUDY. Leukemia,
Vol.7
(1),
pp. 27-8.
NORTON, J.
SLOANE, J.P.
DELIA, D.
GREAVES, M.F.
(1993). RECIPROCAL EXPRESSION OF CD34 AND CELL-ADHESION MOLECULE ELAM-1 ON VASCULAR ENDOTHELIUM IN ACUTE CUTANEOUS GRAFT-VERSUS-HOST DISEASE. Journal of pathology,
Vol.170
(2),
pp. 173-5.
GRIMSLEY, P.G.
AMOS, T.A.
GORDON, M.Y.
GREAVES, M.F.
(1993). RAPID POSITIVE SELECTION OF CD34+ CELLS USING MAGNETIC MICROSPHERES COATED WITH MONOCLONAL-ANTIBODY QBEND 10 LINKED VIA A CLEAVABLE DISULFIDE BOND. Leukemia,
Vol.7
(6),
pp. 898-11.
GREAVES, M.F.
ALEXANDER, F.E.
(1993). AN INFECTIOUS ETIOLOGY FOR COMMON ACUTE LYMPHOBLASTIC-LEUKEMIA IN CHILDHOOD. Leukemia,
Vol.7
(3),
pp. 349-12.
DELIA, D.
LAMPUGNANI, M.G.
RESNATI, M.
DEJANA, E.
AIELLO, A.
FONTANELLA, E.
SOLIGO, D.
PIEROTTI, M.A.
GREAVES, M.F.
(1993). CD34 EXPRESSION IS REGULATED RECIPROCALLY WITH ADHESION MOLECULES IN VASCULAR ENDOTHELIAL-CELLS INVITRO. Blood,
Vol.81
(4),
pp. 1001-8.
GREAVES, M.
(1993). A NATURAL-HISTORY FOR PEDIATRIC ACUTE-LEUKEMIA. Blood,
Vol.82
(4),
pp. 1043-9.
FORD, A.M.
RIDGE, S.A.
CABRERA, M.E.
MAHMOUD, H.
STEEL, C.M.
CHAN, L.C.
GREAVES, M.
(1993). INUTERO REARRANGEMENTS IN THE TRITHORAX-RELATED ONCOGENE IN INFANT LEUKEMIAS. Nature,
Vol.363
(6427),
pp. 358-3.
GRIFFITHS, S.D.
HEALY, L.E.
FORD, A.M.
BENNETT, C.A.
VONCKEN, J.W.
HEISTERKAMP, N.
GROFFEN, J.
GREAVES, M.F.
(1992). CLONAL CHARACTERISTICS OF ACUTE LYMPHOBLASTIC CELLS DERIVED FROM BCR ABL-P190 TRANSGENIC MICE. Oncogene,
Vol.7
(7),
pp. 1391-9.
Monaghan, P.
Robertson, D.
Amos, T.A.
Dyer, M.J.
Mason, D.Y.
Greaves, M.F.
(1992). Ultrastructural localization of bcl-2 protein. J histochem cytochem,
Vol.40
(12),
pp. 1819-1825.
show abstract
Previous cell subfractionation studies have indicated that bcl-2 is an inner mitochondrial membrane protein. We have sought to determine the ultrastructural localization of bcl-2 protein in lymphoma and breast carcinoma cell lines and biopsy material known to overexpress bcl-2 using immunoelectron microscopy. To avoid the possibility of processing artifacts, samples were prepared by three different methods: progressive lowering of temperature, cryosectioning, and freeze-substitution. In all instances the labeling of bcl-2 protein was relatively weak but the distribution the same. In both lymphoma and breast carcinoma tissues, bcl-2 protein was detected on the periphery of mitochondria: little labeling of either the mitochondrial matrix or cristae could be detected. Labeling was also detected on the perinuclear membrane and throughout the cytoplasm, as also indicated by confocal microscopy. These data therefore indicate that bcl-2 protein can be detected at several intracellular sites and that at the likely functional destination, the mitochondria, there appears to be, contrary to expectations, a preferential association with the outer membrane..
JIMENEZ, G.
GRIFFITHS, S.D.
FORD, A.M.
GREAVES, M.F.
ENVER, T.
(1992). ACTIVATION OF THE BETA-GLOBIN LOCUS-CONTROL REGION PRECEDES COMMITMENT TO THE ERYTHROID LINEAGE. Proceedings of the national academy of sciences of the united states of america,
Vol.89
(22),
pp. 10618-5.
full text
VONCKEN, J.W.
GRIFFITHS, S.
GREAVES, M.F.
PATTENGALE, P.K.
HEISTERKAMP, N.
GROFFEN, J.
(1992). RESTRICTED ONCOGENICITY OF BCR ABL P190 IN TRANSGENIC MICE. Cancer research,
Vol.52
(16),
pp. 4534-6.
PRICE, C.M.
KANFER, E.J.
COLMAN, S.M.
WESTWOOD, N.
BARRETT, A.J.
GREAVES, M.F.
(1992). SIMULTANEOUS GENOTYPIC AND IMMUNOPHENOTYPIC ANALYSIS OF INTERPHASE CELLS USING DUAL-COLOR FLUORESCENCE - A DEMONSTRATION OF LINEAGE INVOLVEMENT IN POLYCYTHEMIA-VERA. Blood,
Vol.80
(4),
pp. 1033-6.
FORD, A.M.
HEALY, L.E.
BENNETT, C.A.
NAVARRO, E.
SPOONCER, E.
GREAVES, M.F.
(1992). MULTILINEAGE PHENOTYPES OF INTERLEUKIN-3-DEPENDENT PROGENITOR CELLS. Blood,
Vol.79
(8),
pp. 1962-10.
FORD, A.M.
BENNETT, C.A.
HEALY, L.E.
NAVARRO, E.
SPOONCER, E.
GREAVES, M.F.
(1992). IMMUNOGLOBULIN HEAVY-CHAIN AND CD3 DELTA-CHAIN GENE ENHANCERS ARE DNASE I-HYPERSENSITIVE IN HEMATOPOIETIC PROGENITOR CELLS. Proceedings of the national academy of sciences of the united states of america,
Vol.89
(8),
pp. 3424-5.
GORDON, M.Y.
ATKINSON, J.
CLARKE, D.
DOWDING, C.R.
GOLDMAN, J.M.
GRIMSLEY, P.G.
SICZKOWSKI, M.
GREAVES, M.F.
(1991). DEFICIENCY OF A PHOSPHATIDYLINOSITOL-ANCHORED CELL-ADHESION MOLECULE INFLUENCES HEMATOPOIETIC PROGENITOR BINDING TO MARROW STROMA IN CHRONIC MYELOID-LEUKEMIA. Leukemia,
Vol.5
(8),
pp. 693-6.
HOWELL, S.M.
MOLGAARD, H.V.
GREAVES, M.F.
SPURR, N.K.
(1991). LOCALIZATION OF THE GENE CODING FOR THE HEMATOPOIETIC STEM-CELL ANTIGEN-CD34 TO CHROMOSOME-1Q32. Human genetics,
Vol.87
(5),
pp. 625-3.
BROWN, J.
GREAVES, M.F.
MOLGAARD, H.V.
(1991). THE GENE ENCODING THE STEM-CELL ANTIGEN, CD34, IS CONSERVED IN MOUSE AND EXPRESSED IN HEMATOPOIETIC PROGENITOR-CELL LINES, BRAIN, AND EMBRYONIC FIBROBLASTS. International immunology,
Vol.3
(2),
pp. 175-10.
Cabrera, M.E.
Gray, A.M.
Cartier, L.
Araya, F.
Hirsh, T.
Ford, A.M.
Greaves, M.F.
(1991). Simultaneous adult T-cell leukemia/lymphoma and sub-acute polyneuropathy in a patient from Chile. Leukemia,
Vol.5
(4),
pp. 350-353.
show abstract
This paper reports a case of adult T-cell leukemia/lymphoma associated with human T-cell lymphotropic virus type I (HTLV-I) diagnosed in a Chilean patient who developed after 1 1/2 years a crisis with a progressive sensorimotor polyneuropathy. Serum and cerebrospinal fluid HTLV-I antibody tests were positive and HTLV-I DNA was clonally integrated in peripheral lymphocytes. This case is unusual in having simultaneous neurological disease. Along with other recent data from South America, this suggests that the endemic area of HTLV-I may spread far beyond the Caribbean area..
GREAVES, M.F.
(1990). THE SELLAFIELD CHILDHOOD LEUKEMIA CLUSTER - ARE GERMLINE MUTATIONS RESPONSIBLE. Leukemia,
Vol.4
(6),
pp. 391-6.
GREAVES, M.F.
MCKINNEY, P.F.
(1990). TOWARD A TESTABLE ETIOLOGY OF CHILDHOOD ACUTE LYMPHOBLASTIC-LEUKEMIA - COMMENT. Leukemia,
Vol.4
(7),
pp. 522-1.
FINA, L.
MOLGAARD, H.V.
ROBERTSON, D.
BRADLEY, N.J.
MONAGHAN, P.
DELIA, D.
SUTHERLAND, D.R.
BAKER, M.A.
GREAVES, M.F.
(1990). EXPRESSION OF THE CD34 GENE IN VASCULAR ENDOTHELIAL-CELLS. Blood,
Vol.75
(12),
pp. 2417-10.
GORDON, M.Y.
GREAVES, M.F.
(1989). PHYSIOLOGICAL-MECHANISMS OF STEM-CELL REGULATION IN BONE-MARROW TRANSPLANTATION AND HEMATOPOIESIS. Bone marrow transplantation,
Vol.4
(4),
pp. 335-4.
GORDON, M.Y.
DOWDING, C.R.
RILEY, G.P.
GOLDMAN, J.M.
GREAVES, M.F.
(1989). ADHESIVE DEFECTS IN CHRONIC MYELOID-LEUKEMIA. Current topics in microbiology and immunology,
Vol.149,
pp. 151-5.
MOLGAARD, H.V.
SPURR, N.K.
GREAVES, M.F.
(1989). THE HEMATOPOIETIC STEM-CELL ANTIGEN, CD34, IS ENCODED BY A GENE LOCATED ON CHROMOSOME-1. Leukemia,
Vol.3
(11),
pp. 773-4.
GREAVES, M.F.
(1989). INFECTIVE CAUSE OF CHILDHOOD LEUKEMIA. Lancet,
Vol.1
(8629),
pp. 95-1.
FORD, A.M.
WATT, S.M.
FURLEY, A.J.
MOLGAARD, H.V.
GREAVES, M.F.
(1988). CELL LINEAGE SPECIFICITY OF CHROMATIN CONFIGURATION AROUND THE IMMUNOGLOBULIN HEAVY-CHAIN ENHANCER. Embo journal,
Vol.7
(8),
pp. 2393-7.
BEARPARK, A.D.
GREAVES, M.F.
GORDON, M.Y.
(1988). DEPLETION OF THE CFU-S CONTENT OF MURINE MARROW BY PANNING WITH MURINE AND HUMAN STROMAL LAYERS. British journal of haematology,
Vol.68
(4),
pp. 508-1.
GREAVES, M.F.
(1988). SPECULATIONS ON THE CAUSE OF CHILDHOOD ACUTE LYMPHOBLASTIC-LEUKEMIA. Leukemia,
Vol.2
(2),
pp. 120-6.
ALVEY, P.L.
GREAVES, M.F.
(1987). A COMPUTER-PROGRAM FOR INTERPRETING IMMUNOPHENOTYPIC DATA AS AN AID TO THE DIAGNOSIS OF LEUKEMIA. Leukemia,
Vol.1
(7),
pp. 527-14.
WATT, S.M.
KARHI, K.
GATTER, K.
FURLEY, A.J.
KATZ, F.E.
HEALY, L.E.
ALTASS, L.J.
BRADLEY, N.J.
SUTHERLAND, D.R.
LEVINSKY, R.
GREAVES, M.F.
(1987). DISTRIBUTION AND EPITOPE ANALYSIS OF THE CELL-MEMBRANE GLYCOPROTEIN (HPCA-1) ASSOCIATED WITH HUMAN HEMATOPOIETIC PROGENITOR CELLS. Leukemia,
Vol.1
(5),
pp. 417-10.
CHAN, L.C.
CHEN, P.M.
POWLES, R.
SARAGAS, E.
WIEDEMANN, L.M.
GROFFEN, J.
GREAVES, M.F.
(1987). MOLECULAR LESION IN CHRONIC GRANULOCYTIC-LEUKEMIA IS HIGHLY CONSERVED DESPITE ETHNIC AND GEOGRAPHICAL VARIATION. Leukemia,
Vol.1
(6),
pp. 486-5.
GORDON, M.Y.
RILEY, G.P.
GREAVES, M.F.
(1987). PLASTIC-ADHERENT PROGENITOR CELLS IN HUMAN-BONE MARROW. Experimental hematology,
Vol.15
(7),
pp. 772-7.
MIZUTANI, S.
WATT, S.M.
ROBERTSON, D.
HUSSEIN, S.
HEALY, L.E.
FURLEY, A.J.
GREAVES, M.F.
(1987). CLONING OF HUMAN THYMIC SUBCAPSULAR CORTEX EPITHELIAL-CELLS WITH LYMPHOCYTE-T BINDING-SITES AND HEMATOPOIETIC GROWTH-FACTOR ACTIVITY. Proceedings of the national academy of sciences of the united states of america,
Vol.84
(14),
pp. 4999-5.
full text
WATT, S.M.
KATZ, F.E.
DAVIS, L.
CAPELLARO, D.
GORDON, M.Y.
TINDLE, R.W.
GREAVES, M.F.
(1987). EXPRESSION OF HPCA-1 AND HLA-DR ANTIGENS ON GROWTH FACTOR-DEPENDENT AND STROMA-DEPENDENT COLONY-FORMING CELLS. British journal of haematology,
Vol.66
(2),
pp. 153-7.
GREAVES, M.F.
FURLEY, A.J.
CHAN, L.C.
FORD, A.M.
MOLGAARD, H.V.
(1987). INAPPROPRIATE REARRANGEMENT OF IMMUNOGLOBULIN AND T-CELL RECEPTOR GENES. Immunology today,
Vol.8
(4),
pp. 115-2.
CHAN, L.C.
KARHI, K.K.
RAYTER, S.I.
HEISTERKAMP, N.
ERIDANI, S.
POWLES, R.
LAWLER, S.D.
GROFFEN, J.
FOULKES, J.G.
GREAVES, M.F.
WIEDEMANN, L.M.
(1987). A NOVEL ABL PROTEIN EXPRESSED IN PHILADELPHIA-CHROMOSOME POSITIVE ACUTE LYMPHOBLASTIC-LEUKEMIA. Nature,
Vol.325
(6105),
pp. 635-3.
GORDON, M.Y.
DOWDING, C.R.
RILEY, G.P.
GOLDMAN, J.M.
GREAVES, M.F.
(1987). ALTERED ADHESIVE INTERACTIONS WITH MARROW STROMA OF HEMATOPOIETIC PROGENITOR CELLS IN CHRONIC MYELOID-LEUKEMIA. Nature,
Vol.328
(6128),
pp. 342-3.
GORDON, M.Y.
RILEY, G.P.
WATT, S.M.
GREAVES, M.F.
(1987). COMPARTMENTALIZATION OF A HEMATOPOIETIC GROWTH-FACTOR (GM-CSF) BY GLYCOSAMINOGLYCANS IN THE BONE-MARROW MICROENVIRONMENT. Nature,
Vol.326
(6111),
pp. 403-3.
FURLEY, A.J.
REEVES, B.R.
MIZUTANI, S.
ALTASS, L.J.
WATT, S.M.
JACOB, M.C.
VANDENELSEN, P.
TERHORST, C.
GREAVES, M.F.
(1986). DIVERGENT MOLECULAR PHENOTYPES OF KG1 AND KG1A MYELOID CELL-LINES. Blood,
Vol.68
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pp. 1101-7.
GREAVES, M.F.
MIZUTANI, S.
FURLEY, A.J.
SUTHERLAND, D.R.
CHAN, L.C.
FORD, A.M.
MOLGAARD, H.V.
(1986). DIFFERENTIATION-LINKED GENE REARRANGEMENT AND EXPRESSION IN ACUTE LYMPHOBLASTIC-LEUKEMIA. Clinics in haematology,
Vol.15
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pp. 621-19.
GREAVES, M.F.
CHAN, L.C.
(1986). IS SPONTANEOUS MUTATION THE MAJOR CAUSE OF CHILDHOOD ACUTE LYMPHOBLASTIC-LEUKEMIA. British journal of haematology,
Vol.64
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pp. 1-13.
KATZ, F.E.
WATT, S.M.
MARTIN, H.
LAM, G.
CAPELLARO, D.
GOLDMAN, J.M.
GREAVES, M.F.
(1986). COORDINATE EXPRESSION OF BI 3C5 AND HLA-DR ANTIGENS ON HEMATOPOIETIC PROGENITORS FROM CHRONIC MYELOID-LEUKEMIA. Leukemia research,
Vol.10
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CHAN, L.C.
FURLEY, A.J.
FORD, A.M.
YARDUMIAN, D.A.
GREAVES, M.F.
(1986). CLONAL REARRANGEMENT AND EXPRESSION OF THE T-CELL RECEPTOR BETA-GENE AND INVOLVEMENT OF THE BREAKPOINT CLUSTER REGION IN BLAST CRISIS OF CGL. Blood,
Vol.67
(2),
pp. 533-4.
GREAVES, M.F.
CHAN, L.C.
FURLEY, A.J.
WATT, S.M.
MOLGAARD, H.V.
(1986). LINEAGE PROMISCUITY IN HEMATOPOIETIC DIFFERENTIATION AND LEUKEMIA. Blood,
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pp. 1-11.
MIZUTANI, S.
FORD, A.M.
WIEDEMANN, L.M.
CHAN, L.C.
FURLEY, A.J.
GREAVES, M.F.
MOLGAARD, H.V.
(1986). REARRANGEMENT OF IMMUNOGLOBULIN HEAVY-CHAIN GENES IN HUMAN T-LEUKEMIC CELLS SHOWS PREFERENTIAL UTILIZATION OF THE D-SEGMENT (DQ52) NEAREST TO THE J-REGION. Embo journal,
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pp. 3467-7.
FURLEY, A.J.
MIZUTANI, S.
WEILBAECHER, K.
DHALIWAL, H.S.
FORD, A.M.
CHAN, L.C.
MOLGAARD, H.V.
TOYONAGA, B.
MAK, T.
VANDENELSEN, P.
GOLD, D.
TERHORST, C.
GREAVES, M.F.
(1986). DEVELOPMENTALLY REGULATED REARRANGEMENT AND EXPRESSION OF GENES ENCODING THE T-CELL RECEPTOR-T3 COMPLEX. Cell,
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pp. 75-13.
GREAVES, M.F.
(1986). DIFFERENTIATION-LINKED LEUKEMOGENESIS IN LYMPHOCYTES. Science,
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pp. 697-8.
MILLER, G.J.
PEGRAM, S.M.
KIRKWOOD, B.R.
BECKLES, G.L.
BYAM, N.T.
CLAYDEN, S.A.
KINLEN, L.J.
CHAN, L.C.
CARSON, D.C.
GREAVES, M.F.
(1986). ETHNIC-COMPOSITION, AGE AND SEX, TOGETHER WITH LOCATION AND STANDARD OF HOUSING AS DETERMINANTS OF HLTV-I INFECTION IN AN URBAN TRINIDADIAN COMMUNITY. International journal of cancer,
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pp. 801-8.
Sutherland, D.R.
Bicknell, D.C.
Downward, J.
Parker, P.
Waterfield, M.D.
Baker, M.A.
Greaves, M.F.
Stanbridge, E.J.
(1986). Structural and functional features of a cell surface phosphoglycoprotein associated with tumorigenic phenotype in human fibroblast x HeLa cell hybrids. J biol chem,
Vol.261
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pp. 2418-2424.
show abstract
Monoclonal antibodies have been raised against a dimeric cell surface antigen (p75/150) which is specifically associated with the tumorigenic phenotype in human fibroblast X HeLa hybrids. During biosynthesis, a precursor molecule (p70/140), was associated with microsomal membranes in vivo but possessed no detectable cytoplasmic domains. At this stage, each p70 monomer contained 3 "high-mannose" type N-linked glycans which were subsequently processed into endoglycosidase H-insensitive complex oligosaccharides on the mature cell surface forms. Cleavage of this cell surface form with endoglycosidase F yielded non-N-glycosylated polypeptides of Mr = 60,000/120,000. All the monoclonal antibodies identified similar non-N-glycosylated polypeptides in cells grown in the presence of tunicamycin. p75/150 could be weakly labeled with [3H]palmitic or myristic acid. In vivo, p75/150 was found to be phosphorylated on serine residues. Immunoprecipitates of p75/150 from HeLa or tumorigenic hybrid cell lysates exhibited protein kinase activity in vitro, which phosphorylated p75/150 itself, also on serine residues. We were unable to detect this kinase activity in normal fibroblasts and in the nontumorigenic hybrid cells. Furthermore, we were unable to detect p75/150 or its precursors by either cell surface labeling, metabolic labeling, or Western blotting in nontumorigenic cell hybrids; p75/150 thus represents a tumor-specific marker in this system. Tryptic peptides of highly purified p75/150 have been generated, but their amino acid sequences did not reveal any significant homology with previously described proteins..
MURRAY, L.J.
HABESHAW, J.A.
WIELS, J.
GREAVES, M.F.
(1985). EXPRESSION OF BURKITT LYMPHOMA-ASSOCIATED ANTIGEN (DEFINED BY THE MONOCLONAL ANTIBODY-38 13) ON BOTH NORMAL AND MALIGNANT GERMINAL-CENTER B-CELLS. International journal of cancer,
Vol.36
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pp. 561-5.
CHAN, L.C.
SHEER, D.
DRYSDALE, H.C.
BEVAN, D.
GREAVES, M.F.
(1985). MONOSOMY-7 AND MULTIPOTENTIAL STEM-CELL TRANSFORMATION. British journal of haematology,
Vol.61
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pp. 531-9.
CHAN, L.C.
PEGRAM, S.M.
GREAVES, M.F.
(1985). CONTRIBUTION OF IMMUNOPHENOTYPE TO THE CLASSIFICATION AND DIFFERENTIAL-DIAGNOSIS OF ACUTE-LEUKEMIA. Lancet,
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pp. 475-5.
WEILBAECHER, K.
GREAVES, M.F.
(1985). NAKED BEAUTIES. Nature,
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pp. 196-1.
KATZ, F.E.
TINDLE, R.
SUTHERLAND, D.R.
GREAVES, M.F.
(1985). IDENTIFICATION OF A MEMBRANE GLYCOPROTEIN ASSOCIATED WITH HEMATOPOIETIC PROGENITOR CELLS. Leukemia research,
Vol.9
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pp. 191-8.
MYERS, C.D.
THORPE, P.E.
ROSS, W.C.
CUMBER, A.J.
KATZ, F.E.
TAX, W.
GREAVES, M.F.
(1984). AN IMMUNOTOXIN WITH THERAPEUTIC POTENTIAL IN T-CELL LEUKEMIA - WT1-RICIN-A. Blood,
Vol.63
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JACOBS, P.
GREAVES, M.
(1984). PH1-POSITIVE T-LYMPHOBLASTIC TRANSFORMATION. Leukemia research,
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pp. 737-3.
CHAN, L.C.
GREAVES, M.F.
(1984). ACUTE-LEUKEMIA WITH MIXED LYMPHOID AND MYELOID PHENOTYPE. British journal of haematology,
Vol.58
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pp. 203-2.
DALGLEISH, A.G.
BEVERLEY, P.C.
CLAPHAM, P.R.
CRAWFORD, D.H.
GREAVES, M.F.
WEISS, R.A.
(1984). THE CD4 (T4) ANTIGEN IS AN ESSENTIAL COMPONENT OF THE RECEPTOR FOR THE AIDS RETROVIRUS. Nature,
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pp. 763-5.
GREAVES, M.F.
SIEFF, C.
EDWARDS, P.A.
(1983). MONOCLONAL ANTIGLYCOPHORIN AS A PROBE FOR ERYTHROLEUKEMIAS. Blood,
Vol.61
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pp. 645-7.
Ford, A.M.
Molgaard, H.V.
Greaves, M.F.
Gould, H.J.
(1983). Immunoglobulin gene organisation and expression in haematopoietic stem cell leukaemia. Embo j,
Vol.2,
pp. 997-1001.
ROBINSON, J.
SIEFF, C.
DELIA, D.
EDWARDS, P.A.
GREAVES, M.
(1981). EXPRESSION OF CELL-SURFACE HLA-DR, HLA-ABC AND GLYCOPHORIN DURING ERYTHROID-DIFFERENTIATION. Nature,
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GREAVES, M.F.
JANOSSY, G.
PETO, J.
KAY, H.
(1981). IMMUNOLOGICALLY DEFINED SUBCLASSES OF ACUTE LYMPHOBLASTIC-LEUKEMIA IN CHILDREN - THEIR RELATIONSHIP TO PRESENTATION FEATURES AND PROGNOSIS. British journal of haematology,
Vol.48
(2),
pp. 179-19.
GREAVES, M.F.
ROBINSON, J.
SUTHERLAND, R.
NEWMAN, R.A.
GOLDSTEIN, G.
KUNG, P.
EDWARDS, P.
MCMICHAEL, A.
(1981). A LIBRARY OF MONOCLONAL-ANTIBODIES AGAINST HUMAN HEMATOPOIETIC-CELLS - ANALYSIS OF ANTIGEN EXPRESSION DURING EARLY HEMATOPOIETIC DIFFERENTIATION AND APPLICATION TO THE DIFFERENTIAL-DIAGNOSIS OF LEUKEMIA. British journal of cancer,
Vol.43
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pp. 564-2.
NEWMAN, R.A.
ORMEROD, M.G.
GREAVES, M.F.
(1980). THE PRESENCE OF HLA-DR ANTIGENS ON LACTATING HUMAN-BREAST EPITHELIUM AND MILK-FAT GLOBULE MEMBRANES. Clinical and experimental immunology,
Vol.41
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pp. 478-9.
JANOSSY, G.
HOFFBRAND, A.V.
GREAVES, M.F.
GANESHAGURU, K.
PAIN, C.
BRADSTOCK, K.F.
PRENTICE, H.G.
KAY, H.E.
LISTER, T.A.
(1980). TERMINAL TRANSFERASE ENZYME ASSAY AND IMMUNOLOGICAL MEMBRANE MARKERS IN THE DIAGNOSIS OF LEUKEMIA - MULTI-PARAMETER ANALYSIS OF 300 CASES. British journal of haematology,
Vol.44
(2),
pp. 221-0.
GREAVES, M.
DELIA, D.
JANOSSY, G.
RAPSON, N.
CHESSELLS, J.
WOODS, M.
PRENTICE, G.
(1980). ACUTE LYMPHOBLASTIC-LEUKEMIA ASSOCIATED ANTIGEN 4 EXPRESSION ON NON-LEUKEMIC LYMPHOID-CELLS. Leukemia res,
Vol.4
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pp. 15-32.
GREAVES, M.F.
VERBI, W.
REEVES, B.R.
HOFFBRAND, A.V.
DRYSDALE, H.C.
JONES, L.
SACKER, L.S.
SAMARATUNGA, I.
(1979). PRE-B PHENOTYPES IN BLAST CRISIS OF PH1 POSITIVE CML - EVIDENCE FOR A PLURIPOTENTIAL STEM-CELL TARGET. Leukemia research,
Vol.3
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pp. 181-0.
JANOSSY, G.
ROBERTS, M.
GREAVES, M.F.
WOODRUFF, R.
PIPPARD, M.
PRENTICE, G.
HOFFBRAND, A.V.
(1978). LYMPHOID BLAST CRISIS IN CHRONIC MYELOID-LEUKEMIA AND PHILADELPHIA POSITIVE ACUTE LYMPHOID LEUKEMIA. Bollettino dell istituto sieroterapico milanese,
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pp. 355-5.
CATOVSKY, D.
GREAVES, M.F.
PAIN, C.
CHERCHI, M.
JANOSSY, G.
KAY, H.E.
(1978). ACID-PHOSPHATASE REACTION IN ACUTE LYMPHOBLASTIC LEUKEMIA. Lancet,
Vol.1
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pp. 749-3.
DOENHOFF, M.J.
JANOSSY, G.
GREAVES, M.F.
GOMER, K.J.
SNAJDR, J.
(1974). LYMPHOCYTE-ACTIVATION 6 RE-EVALUATION OF FACTORS AFFECTING SELECTIVITY OF POLYCLONAL MITOGENS FOR MOUSE T AND B CELLS. Clinical and experimental immunology,
Vol.17
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pp. 475-16.
Zuna, J.
Ford, A.M.
Peham, M.
Patel, N.
Saha, V.
Eckert, C.
Kochling, J.
Panzer-Grumayer, R.
Trka, J.
Greaves, M.
TEL deletion analysis supports a novel view of relapse in childhood acute lymphoblastic leukemia. Clin cancer res,
Vol.10,
pp. 5355-5360.
Kempski, H.
Mensa-Bonsu, K.A.
Kearney, L.
Jalali, G.R.
Hann, I.
Khurshid, M.
Greaves, M.F.
Prenatal chromosomal diversification of leukemia in monozygotic twins. Genes chromosomes cancer,
Vol.37,
pp. 406-411.
Jalali, G.R.
Martineau, M.
Ford, A.M.
Greaves, M.F.
Stevens, R.F.
Harrison, C.J.
A unique variant of ETV6/AML1 fusion in a child with acute lymphoblastic leukemia. Leukemia,
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pp. 993-995.