Abstract 4754: Investigating the impact of hotspot mutations in a chromatin reader on leukemogenesis

Abstract

Abstract Acute myeloid leukemia (AML) is one of the most aggressive forms of hematological malignancies with a low overall 5-year survival rate (< 26%). The mainstay of treatment for AML includes chemotherapy, but the response of a subset of patients to current treatment options remains poor. Thus, new therapeutic approaches are desperately needed. AML often arises from somatic mutations in chromatin regulators that result in uncontrolled proliferation and a block of differentiation in myeloid progenitor cells. As such, investigation of the role and molecular mechanism of chromatin regulator in AML is being actively pursued. Previously, we discovered the eleven-nineteen-leukemia (ENL) protein, a chromatin “reader” and transcription co-activator, as an unrecognized requirement for the survival of AML. We developed a potent and orally bioavailable small-molecule inhibitor of ENL, which displaces ENL from chromatin and blocks AML progression. Hotspot mutations have been found in ENL YEATS domains, both in Wilms tumor and in leukemia, and these mutations confer a gain of condensation property, leading to aberrant gene activation. However, the impact of ENL mutation on tumorigenesis is largely unknown. The over-arching goal of this project is to explore the impact of the hyper-activated ENL pathway (ENL mutation) in AML. Results from this project will elucidate how newly discovered chromatin reader mutations drive tumorigenesis and offer new biology insights that will facilitate both basic mechanistic studies and clinical studies. Citation Format: Yiman Liu, Qinglan Li, Sylvia Tang, Chujie Gong, Liling Wan. Investigating the impact of hotspot mutations in a chromatin reader on leukemogenesis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4754.