Decoding the Molecular Mechanisms Underlying NPM1-mutation-driven Leukemogenesis

Dr. Zhang’s proposed Young Investigator project is focused on what causes myeloid progenitor cells to become leukemic cells, developing into Acute Myeloid Leukemia.  She notes that a mutation in a certain gene, NPM1, is found in more than 30% of new AML cases and that while these patients are responsive to therapy, roughly a third of them will relapse, particularly those where the NPM1 mutation causes a cytoplasmic mutation of the protein that NPM1 produces, designated NPM1c . Additionally, NPM1c often occurs alongside age-related clonal hematopoiesis-associated mutations; the NPM1c mutation is often found together with epigenetic modifier mutations and is rarely present with non-epigenetic modifier mutations, suggesting that a specific epigenetic landscape is required for NPM1c driven leukemias.

These findings cause Dr. Zhang to hypothesize that the development of NPM1c driven leukemia requires certain chromatin changes and that leukemogenesis though NPM1c also likely requires epigenetic modifications through post-translational changes. Using  a number of cutting-edge sequencing and assay tools,  Dr. Zhang hopes to describe both the prerequisites and key regulators for NPM1c driven leukemia.  She will investigate the role of remodeled chromatin and intensified stress response in allowing leukemogenesis. Dr. Zhang plans to clarify both the transcriptional and post-translational regulators linked to leukemia development and will test the relevance of her findings through both genetic and pharmaceutical approaches. The ultimate goal of this project is to understand the molecular and structural  prerequisites for NPM1c to allow us to better fully eradicate NPM1c leukemic stem cells, leading to remission-free treatment of NPM1c AML and significantly improved patient outcomes.