mutations define the commonest subgroup of acute myeloid leukemia (AML) and frequently co-occur with internal tandem duplications (ITD) or, less commonly, or mutations. Co-occurrence of mutant with carries a significantly worse prognosis than combinations. To understand the molecular basis of these observations, we compare the effects of the 2 combinations on hematopoiesis and leukemogenesis in knock-in mice. Early effects of these mutations on hematopoiesis show that compound or share a number of features: gene overexpression, enhanced self-renewal, expansion of hematopoietic progenitors, and myeloid differentiation bias. However, mutants displayed significantly higher peripheral leukocyte counts, early depletion of common lymphoid progenitors, and a monocytic bias in comparison with the granulocytic bias in mutants. Underlying this was a striking molecular synergy manifested as a dramatically altered gene expression profile in , but not , progenitors compared with wild-type. Both double-mutant models developed high-penetrance AML, although latency was significantly longer with During AML evolution, both models acquired additional copies of the mutant or alleles, but only mice showed acquisition of other human AML mutations, including R132Q. We also find, using primary Cas9-expressing AMLs, that genes and selected interactors or downstream targets are required for survival of both types of double-mutant AML. Our results show that molecular complementarity underlies the higher frequency and significantly worse prognosis associated with c/ vs mutant AML and functionally confirm the role of genes in NPM1c-driven AML.     «

mutations define the commonest subgroup of acute myeloid leukemia (AML) and frequently co-occur with internal tandem duplications (ITD) or, less commonly, or mutations. Co-occurrence of mutant with carries a significantly worse prognosis than combinations. To understand the molecular basis of these observations, we compare the effects of the 2 combinations on hematopoiesis and leukemogenesis in knock-in mice. Early effects of these mutations on hematopoiesis show that compound or share...     »