Linde Miles, PhD

Acute myeloid leukemia (AML) is a diverse set of blood malignancies that ultimately leads to a build-up of immature blood cells at the expense of mature functioning blood cells. The NPM1 gene is mutated in 20-35% of AML and defines a specific subset of AML patients. However, it is unclear exactly how mutant NPM1 (NPM1c) drives leukemia development and whether the imparted changes that occur within cells due to NPM1 mutations are reversible and/or crucial for cell survival. Moreover, it is not understood how co-mutations affect a cell’s dependency on mutant NPM1c protein. Recently, inhibitors of a protein complex, menin/MLL, have been shown to be effective in NPM1-mutant AML patients, but the totality of the connection between the inhibition of menin and inhibition of all Npm1c-dependent programs remains unexplored. Using a novel mouse model of mutant Npm1c, this proposal aims to define the cellular consequences of Npm1c mutation and whether loss or inhibition of Npm1c affects these atypical changes. These studies will improve the understanding of NPM1-mutant AML and has the potential to uncover novel therapeutic targets for AML patients harboring an NPM1c mutation.