Investigating the impact of hotspot mutations in a chromatin reader on leukemogenesis
Yiman Liu
PhDPerelman School of Medicine at the University of Pennsylvania
Project Term: July 1, 2023 - June 30, 2025
The goal of this proposal is to investigate the consequence of the chromatin reader eleven-nineteen-leukemia (ENL) gain-of-function mutations in the pathogenesis of leukemia. Our studies leverage the expertise in the molecular and chromatin biology of chromatin reader in leukemia utilizing mouse model, high resolution image, epigenomic and transcriptomic approaches. Our goal is to understand how chromatin reader contributes to cancer development, progression, and therapeutic outcome.
Acute myeloid leukemia, arising from abnormal blood cells, has one of the lowest five-year survival rates (26%) of all cancers. The mainstay of treatment for acute myeloid leukemia includes chemotherapy, but the response of a subset of patients to chemotherapy remains poor. Thus, understand the pathogenesis of acute myeloid leukemia and provide new therapeutic approaches are desperately needed. Acute myeloid leukemia often arises from mutations in chromatin regulators (e.g., NPM1 mutations, DNMT3A mutations) that result in uncontrolled blood cell proliferation. Chromatin regulators are the master controllers of gene expression in cells through regulation of chromatin. In this proposal, we are investigating the function and regulation of chromatin regulator in acute myeloid leukemia. Previously, we discovered the eleven-nineteen-leukemia (ENL) protein, a chromatin regulator which could mediate leukemia cell growth. Furthermore, we developed a potent and orally small-molecule inhibitor of ENL, which could inhibit leukemia cell growth and block acute myeloid leukemia progression. Hotspot mutations have been found in ENL in Wilms tumor and leukemia, our lab have demonstrated that these mutations lead to hyper-activation of ENL pathway. However, the impact of ENL mutation on cancer development and progress is largely unknown. The over-arching goal of this project is to explore the effect of hyper-activation of ENL pathway on acute myeloid leukemia development and progression. In addition, our study will also provide a novel regulation pattern by ENL mutation in acute myeloid leukemia. Altogether, this proposal will not only provide important biological insights into the understanding of how chromatin regulators are involved in acute myeloid leukemia develop but will provide new therapeutic approach for acute myeloid leukemia patients who are poorly respond to chemotherapy