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MEF2D-Mediated Transcriptional Control of Acute Myeloid Leukemia

Award Number: R01CA259480
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/20/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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MEF2D-Mediated Transcriptional Control of Acute Myeloid Leukemia - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $345,047 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Biology Research	001	4	6/18/2025	NON-COMPETING CONTINUATION	$34,506
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Biology Research	000	4	12/3/2024	NON-COMPETING CONTINUATION	$310,541
														Subtotal = $345,047

Issue Date FY: 2024 ( Subtotal = $327,794 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Biology Research	000	3	11/29/2023	NON-COMPETING CONTINUATION	$310,541
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Biology Research	001	3	4/17/2024	NON-COMPETING CONTINUATION	$17,253
														Subtotal = $327,794

Issue Date FY: 2023 ( Subtotal = $339,156 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Biology Research	001	2	3/17/2023	NON-COMPETING CONTINUATION	$27,687
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Biology Research	000	2	11/18/2022	NON-COMPETING CONTINUATION	$311,469
														Subtotal = $339,156

Issue Date FY: 2022 ( Subtotal = $356,141 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Biology Research	000	1	12/20/2021	NEW	$356,141
														Subtotal = $356,141

Grand Total All Awards = $1,368,138

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MEF2D-Mediated Transcriptional Control of Acute Myeloid Leukemia

Award Number: R01CA259480

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/20/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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