Fanconi anemia (FA) is an inherited disorder of genomic instability associated with high risk of myelodysplasia and AML. Young mice deficient in FA core complex genes do not naturally develop cancer, hampering preclinical studies on malignant hematopoiesis in FA. Here we show that aging Fancc-/- mice are prone to genomically unstable AML and other hematologic neoplasms. We demonstrate that aneuploidy precedes malignant transformation during Fancc-/- hematopoiesis. Our observations reveal that Fancc-/- mice develop hematopoietic chromosomal instability followed by leukemia in age-dependent manner, recapitulating the clinical phenotype of human Fanconi anemia and providing a proof of concept for future development of preclinical models of FA-associated leukemogenesis.