<p>Genetic studies have identified recurrent somatic mutations in acute myeloid leukemia (AML) patients, including in the Wilms' tumor 1 () gene. The molecular mechanisms by which mutations contribute to leukemogenesis have not yet been fully elucidated. We investigated the role of gene dosage in steady-state and pathologic hematopoiesis. 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. -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 depletion cooperates with mutation to induce fully penetrant AML. Our studies provide insight into mechanisms of -loss leukemogenesis and into the evolutionary events required to induce transformation of -haploinsufficient stem/progenitor cells.</p>