Genetic and epigenetic evolution as a contributor to WT1-mutant leukemogenesis Academic Article uri icon

Overview

MeSH Major

  • Janus Kinase 2
  • Primary Myelofibrosis
  • Pyrazoles
  • Pyrimidines
  • Spleen
  • Stem Cells

abstract

  • Copyright 2011 by The American Society of Hematology; all rights reserved. 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.

publication date

  • September 20, 2018

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC6148447

Digital Object Identifier (DOI)

  • 10.1182/blood-2018-03-837468

PubMed ID

  • 30064973

Additional Document Info

start page

  • 1265

end page

  • 1278

volume

  • 132

number

  • 12