Epigenetic Mechanisms in Acute Myeloid Leukemia
Liling Wan
PhDPerelman School of Medicine at the University of Pennsylvania
Project Term: July 1, 2023 - June 30, 2028
The goal of this project is to investigate the role of the epigenetic regulator Eleven-Nineteen-Leukemia (ENL) and its cancer mutations in acute myeloid leukemia (AML). Our studies leverage the expertise in chromatin biology, functional genomics, and AML modeling, as well as unique chemical compounds and mouse models. Results from this project will provide novel biological insights into our understanding of AML pathogenesis and facilitate the development of novel epigenetic therapies.
Acute myeloid leukemia (AML), arising from abnormal, immature white blood cells, has one of the lowest five-year survival rates (26%) of all cancers, so new treatment strategies are desperately needed. Epigenetics refers to the regulation of gene expression mainly through changes in modifications on DNA and histone proteins without changing the underlying DNA sequences. AML often results from aberrant function of epigenetic regulators, leading to activating or repressing the wrong genes at the wrong time and in the wrong cell. AML cells also heavily rely on the function of certain epigenetic regulators for their uncontrolled growth. The overall goal of our program is to better understand epigenetic mechanisms that contribute to AML development and progression in order to uncover new therapeutic strategies. In this project, we will study the role of the epigenetic regulator Eleven-Nineteen-Leukemia (ENL) and its mutations in AML. Our previous studies have found that a subset of AML cells rely on the function of the ENL protein to live. And quite excitingly, a chemical compound we developed to block ENL’s function can inhibit AML grown in mice. Recently, mutations in the ENL gene are found in patients with AML and other cancers. We have found that these mutations create an over-activated form of ENL which, when introduced to mice, can give rise to aggressive AML. In this project, we aim to (1) understand why some AML rely on ENL to survive and some do not in order to better stratify patients for future clinical studies, and (2) find out the mechanisms by which ENL mutations drive leukemia using a novel mouse model we have developed. Altogether, this work will not only help us understand better how AML develops and progresses but also provide needed biological insights to guide ongoing development of ENL inhibitors as potential new weapons against difficult-to-treat blood cancers. We are hopeful that our findings could lead to improvements in the lives of a subset of AML patients.