Year 1, Lay Summary: Our awarded proposal focuses on understanding the dependency of acute myeloid leukemia (AML) cells on a particular mutant oncogene, NPM1c, which is mutated in approximately 30% of AML patients. We have made significant progress on our specific goals during the 1 st year of this award. Through cellular assays and in vivo studies with innovative AML mouse models, which harbor mutational combinations we frequently observe in NPM1c-mutant AML patients, we have found that loss of mutant Npm1c in Npm1c-mutant AML cells indeed adversely affects cellular fitness. Moreover, we have begun studies with menin inhibition, which is currently showing clinical promise in NPM1-mutant AML patients and indirectly abrogates mutant Npm1c-related pathways through disruption of the interaction between menin and the MLL protein. Ongoing and future studies for the next year of the award will focus on dissecting the mechanisms behind our current observations to uncover Npm1c-dependent pathways.

Year 2, Lay Summary: Our awarded proposal focuses on understanding the dependency of acute myeloid leukemia (AML) cells on a particular mutant oncogene, NPM1c, which is mutated in approximately 30% of AML patients. We have made significant progress on our specific goals during the 2nd year of this award. Through in vivo studies with our novel Npm1c mouse model, we have found that loss of mutant Npm1c in Npm1c-mutant AML cells indeed adversely affects leukemic cellular fitness. However, by combining this mouse model with different co-occurring mutations observed in human AML patients, we have observed that the presence of certain mutations can affect the dependency of the leukemic cell on Npm1c and therefore affect the effect of Npm1c loss on leukemic maintenance. Moreover, we have shown that there are divergent cellular responses between the loss of Npm1c itself and inhibition of mutant Npm1c-related pathways through menin inhibition, which is currently a FDA approved treatment strategy for NPM1c-mutant AML patients. These findings suggest that there may be critical functions of Npm1c important for leukemic cell survival outside of its interaction with the menin/MLL protein complex. Ongoing and future studies for the next year of the award will focus on dissecting the mechanisms behind our current observations to uncover Npm1c-dependent pathways.