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

Elodie Pronier, Robert L. Bowman, Jihae Ahn, Jacob Glass, Cyriac Kandoth, Tiffany R. Merlinsky, Justin T. Whitfield, Benjamin H. Durham, Antoine Gruet, Amritha Varshini Hanasoge Somasundara, Raajit Rampal, Ari Melnick, Richard P. Koche, Barry S. Taylor and Ross L. Levine

Key points

  • Wt1 heterozygous loss enhanced stem cell self-renewal in an age-dependent manner.

  • Wt1-haploinsufficient leukemias require additional events to promote hematopoietic transformation.

Abstract

Genetic studies have identified recurrent somatic mutations in Acute Myeloid Leukemia (AML) patients, including in the WT1 (Wilms' tumor 1) 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 (Fms-like tyrosine kinase 3) 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.

  • Submitted March 5, 2018.
  • Accepted July 5, 2018.