MEF2D-Mediated Transcriptional Control of Acute Myeloid Leukemia

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) with MLL (KMT2A) gene rearrangement (MLL-r) is an aggressive disease with uncontrolled proliferation of myeloid progenitor cells and a failure of proper cell differentiation. Despite conventional chemotherapy, the overall survival of MLL-r AML remains poor and therapeutic options are limited, highlighting an unmet need to understand MLL-r AML pathogenesis and discover new genetic vulnerabilities. MEF2 transcriptional factors (MEF2A, 2B, 2C, and 2D) play important functions in the development of muscle, neuronal, and lymphoid lineages. Despite the known role of MEF2C as a direct MLL-r target essential for leukemogenesis, it remains unknown whether additional MEF2 family members are deregulated or involved in MLL-r leukemia. In this study, we identified that MEF2D gains aberrant super-enhancers and is highly upregulated in MLL-r AML. We demonstrate that MEF2D is selectively required for MLL-r AML, and depletion of MEF2D results in profound leukemia differentiation through transcriptional repression of CEBPE. We further show the MEF2D-CEBPE axis is critically involved in the anti-leukemia effects of DOT1L and Menin inhibitors. Furthermore, we discovered a novel interdependency of MEF2 paralogs in MLL-r AML. These preliminary data have provided us scientific rationale and enthusiasm for our central hypothesis that MEF2D, a novel transcriptional dependency highly expressed in MLL-r AML, maintains leukemia through inhibition of a CEBPE- centered myeloid differentiation program. This hypothesis is supported by extensive preliminary data and will be further tested by two specific aims: (1) establish the oncogenic function of MEF2D in MLL-r leukemogenesis and therapeutic response, and (2) investigate the mechanisms of MEF2D-mediated oncogenic regulation in MLL-r AML. In Specific Aim 1, we will determine the role of MEF2D in our pre-established genetically defined AML mouse models in vitro and in vivo; we will also evaluate the role of MEF2D-CEBPE axis in Menin inhibitor- mediated anti-leukemia effects. In Specific Aim 2, we will determine the molecular mechanisms by which MEF2D represses CEBPE, define MEF2D target genes using unbiased genome approaches, and evaluate the role of MEF2D-MEF2C interaction in MLL-r AML. The long-term goal of this project is to understand the MEF2 regulatory network in MLL-r AML, and to develop novel therapeutic approaches targeting oncogenic MEF2 factors for leukemia therapy. The main objective of this proposal is to establish the oncogenic function of MEF2D and determine how it regulates leukemia cell self-renewal and differentiation. Results from this proposal will provide significant new knowledge on the critical role of MEF2D in AML, reveal a new mechanism for suppression of normal hematopoietic differentiation in leukemia, and serve as the basis for targeting MEF2-related pathways as a potential therapeutic strategy for AML patients.