| First Author | Pronier E | Year | 2018 |
| Journal | Blood | Volume | 132 |
| Issue | 12 | Pages | 1265-1278 |
| PubMed ID | 30064973 | Mgi Jnum | J:265991 |
| Mgi Id | MGI:6201822 | Doi | 10.1182/blood-2018-03-837468 |
| Citation | Pronier E, et al. (2018) Genetic and epigenetic evolution as a contributor to WT1-mutant leukemogenesis. Blood 132(12):1265-1278 |
| abstractText | 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. |
