Mel Greaves

..We argue that these insights provide a very useful framework for attempts to understand etiologic mechanisms...

..How, when and where do translocations arise? And can these insights aid our understanding of the natural history, pathogenesis and causes of leukaemia?..

..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...

..Another study, in contrast, suggests that B-CLL cells uniquely acquire the ability to signal in the complete absence of ligand...

..These natural histories provide an important framework for consideration of key aetiological events in paediatric leukaemia...

..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...

..These natural histories provide an important framework for consideration of key etiological events in pediatric leukemia...

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..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...

..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...

..This phenotype is associated with an altered pattern of cell cycle arrest and/or apoptosis...

..Our results, and other recent data, provide a mechanism for oncogenic conversion of MLL by fusion partners encoding cytoplasmic proteins...

..These data place all "driver" CNAs secondary to the prenatal gene fusion event and most probably postnatal in the sequential, molecular pathogenesis of ALL...

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..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...

..Further elaboration of the biology of MLL gene-associated leukemia should lead to novel and specific therapeutic strategies...

..These results infer a complex molecular pathogenesis for DS-ALL leukemogenesis, with trisomy 21 as an initiating or first hit and with chromosome aneuploidy, gene deletions, and activating JAK2 mutations as complementary genetic events...

..We conclude that major histocompatibility complex-defined variation in immune-mediated response is unlikely to be a major risk factor for BCP-ALL...

..These data have implications for cancer genomics and for the targeted therapy of cancer...

..These data support the contention that ETV6-RUNX1 directly activates ectopic expression of a functional EPOR and provides cell survival signals that may contribute critically to persistence of covert premalignant clones in children...

..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...

..Notably, all three risk variants map to genes involved in transcriptional regulation and differentiation of B-cell progenitors...

..We present evidence that the duration of the postnatal preleukemic state can occasionally be very protracted in these biological subtypes of pediatric leukemia, and we discuss its biological significance...

..These data have implications for the biology of ALL and for management of similar patients...

..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...

..This case of leukemia illustrates in utero initiation with early imposition of chromosomal instability, the progressively divergent evolution of which can be mapped in the twins into pre- and postnatal periods...

..We conclude that NOTCH1 can be an early or initiating event in T-ALL arising prenatally, to be complemented by a postnatal SIL-TAL1 fusion...

..This consistent sequence of molecular pathogenesis facilitates an analysis of the clonal origins of relapse in this leukemia, which has some unusual clinical features...

..We review here progress in tackling these questions...

..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...

..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...

..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...

..Now, however, we can provide direct evidence of this from our identification of CD34+/CD19+ B-lineage progenitor cells with triploid chromosomes in the stored cord blood of an individual who subsequently developed hyperdiploid ALL...

..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...

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..A case is made here for a Darwinian perspective on breast and prostate cancers, for which current understanding of causation is limited and contentious...

..These results suggest that HDAC9 plays a role in hematopoiesis; its deregulated expression may be associated with some human cancers...

..These results provide support for the delayed exposure hypothesis in an affluent geographical setting in which population exposure to infectious agents is quite distinct from the settings of previous case-control studies...

..Systematic sequencing of cancer genomes therefore reveals the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated...