New Investigator Research Grant Program

Acute myeloid leukemia (AML) is a highly aggressive blood cancer driven by acquired genetic abnormalities in hematopoietic stem and progenitor cells (HSPCs), leading to their transformation into leukemic stem cells (LSCs). Among AML-defining mutations, Nucleophosmin 1 (NPM1) mutations are the most prevalent, occurring in approximately 30% of adult de novo AML cases. These mutations mislocalize NPM1 to the cytoplasm (NPM1c), which drives leukemogenesis via various mechanisms including sustained HOX activation. While NPM1-mutant AML is often associated with a favorable prognosis, more than 30% of patients experience relapse and poor survival, despite receiving conventional or targeted therapies. This suggests that NPM1c+ LSCs are not completely eradicated, underscoring the urgent need to understand the precise mechanisms by which NPM1c promotes leukemogenesis. Using genetic models, we have identified that Hox-independent mechanisms are also essential for Npm1c-driven leukemogenesis. These mechanisms allow Npm1c+ LSCs to bypass p53 activation via balanced transcriptional demands and translation capacities, at least in part via metabolic reprogramming. Our work aims to identify regulators that permit NPM1c-driven leukemogenesis at transcriptional and post-translational levels to inform new therapeutic approaches for improved patient outcomes.