Genetic and epigenetic evolution as a contributor to WT1-mutant leukemogenesis.
| Publication Type | Academic Article |
| Authors | Pronier E, Bowman R, Ahn J, Glass J, Kandoth C, Merlinsky T, Whitfield J, Durham B, Gruet A, Hanasoge Somasundara A, Rampal R, Melnick A, Koche R, Taylor B, Levine R |
| Journal | Blood |
| Volume | 132 |
| Issue | 12 |
| Pagination | 1265-1278 |
| Date Published | 07/31/2018 |
| ISSN | 1528-0020 |
| Keywords | Epigenesis, Genetic, Gene Expression Regulation, Leukemic, Leukemia, Myeloid, Acute, Mutation, Repressor Proteins |
| 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. |
| DOI | 10.1182/blood-2018-03-837468 |
| PubMed ID | 30064973 |
| PubMed Central ID | PMC6148447 |