Genetic and epigenetic evolution as a contributor to WT1-mutant leukemogenesis Journal Article

Authors: Pronier, E.; Bowman, R. L.; Ahn, J.; Glass, J.; Kandoth, C.; Merlinsky, T. R.; Whitfield, J. T.; Durham, B. H.; Gruet, A.; Hanasoge Somasundara, A. V.; Rampal, R.; Melnick, A.; Koche, R. P.; Taylor, B. S.; Levine, R. L.
Article Title: Genetic and epigenetic evolution as a contributor to WT1-mutant leukemogenesis
Abstract: Genetic studies have identified recurrent somatic mutations in acute myeloid leukemia (AML) patients, including in the Wilms’ tumor 1 (WT1) gene. The molecular mechanisms by which WT1 mutations contribute to leukemogenesis have not yet been fully elucidated. We investigated the role of Wt1 gene dosage in steady-state and pathologic hematopoiesis. Wt1 heterozygous loss enhanced stem cell self-renewal in an age-dependent manner, which increased stem cell function over time and resulted in age-dependent leukemic transformation. Wt1-haploinsufficient leukemias were characterized by progressive genetic and epigenetic alterations, including those in known leukemia-associated alleles, demonstrating a requirement for additional events to promote hematopoietic transformation. Consistent with this observation, we found that Wt1 depletion cooperates with Flt3-ITD mutation to induce fully penetrant AML. Our studies provide insight into mechanisms of Wt1-loss leukemogenesis and into the evolutionary events required to induce transformation of Wt1-haploinsufficient stem/progenitor cells. Copyright 2011 by The American Society of Hematology; all rights reserved.
Journal Title: Blood
Volume: 132
Issue: 12
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2018-09-20
Start Page: 1265
End Page: 1278
Language: English
DOI: 10.1182/blood-2018-03-837468
PROVIDER: scopus
PMCID: PMC6148447
PUBMED: 30064973
Notes: Article -- Export Date: 1 November 2018 -- Source: Scopus
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MSK Authors
  1. Raajit Kumar Rampal
    128 Rampal
  2. Ross Levine
    469 Levine
  3. Barry Stephen Taylor
    138 Taylor
  4. Robert L Bowman
    22 Bowman
  5. Jihae Ahn
    11 Ahn
  6. Richard Patrick Koche
    48 Koche
  7. Jacob Lowell Glass
    13 Glass
  8. Benjamin Heath Durham
    60 Durham
  9. Cyriac Kandoth
    17 Kandoth
  10. Antoine Gruet
    3 Gruet