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Functionally dissecting MECOM gene regulation in high-risk leukemia

Award Number: F31CA287658
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/01/2024
PERIOD OF PERFORMANCE END DATE: 05/29/2025

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Functionally dissecting MECOM gene regulation in high-risk leukemia - PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is a devastating disease that continues to have a poor prognosis with less than one-third of patients achieving a cure from their disease. While the identification of genomic subtypes has enabled some risk stratification, it is increasingly evident that variation in cell states in AML and particularly the presence of leukemia progenitors that co-opt hematopoietic stem cell (HSC) programs appear to confer a particularly poor prognosis. Despite these robust descriptive observations, however, the molecular drivers of these high-risk gene expression programs that alter cell state have remained largely undefined. Our research group recently characterized a gene network that is regulated by the HSC master transcription factor MECOM and co-opted in high-risk forms of AML. However, we still lack an understanding of the mechanisms by which MECOM regulates this network and how it can be therapeutically hijacked to improve treatment of leukemias. To better interrogate MECOM’s direct function in AML, we engineered an AML cell-line model in which MECOM can be rapidly and controllably degraded by addition of a small molecule. Assessments of changes in transcription and chromatin accessibility immediately following complete MECOM degradation implicate MECOM as an epigenetic repressor of a pro-myeloid differentiation program. Importantly, the majority of these differentially accessible chromatin regions are also directly bound by MECOM in the absence of degradation, suggesting that these observed changes are a direct consequence of MECOM ablation. The observed repressive function of MECOM is also consistent with its reported interactions with the CtBP family of co-repressive factors. However, there are fundamental knowledge gaps both in the identity of MECOM’s direct targets across primary AMLs and the mechanisms underlying its repressive function, both of which could be therapeutically useful. This study consists of two aims to investigate: (1) the identity of genetic targets directly regulated by MECOM function in high-risk AMLs, and (2) the epigenetic mechanisms by which MECOM represses differentiation programs to maintain AML progenitor cells. For this F31 award, the PI has designed a research strategy and training program that will provide him with: (1) fundamental expertise in genomics, bioinformatics, and cancer biology, (2) an expert group of mentors and collaborators to promote not only research expertise, but also career-long academic skills including grantsmanship and scientific communication, and (3) experience performing rigorous, mechanistic and foundational biomedical research in preparation for his career goal as an academic scientist. This proposal will take place in the rich and collaborative Harvard Medical School and Boston Children’s Hospital research environments. Completion of this work is expected to identify the direct transcriptional targets of MECOM in high-risk AML and elucidate the epigenetic mechanisms by which MECOM drives leukemogenesis. These results will have profound implications for the rationale pursuit of high-confidence, tractable targets that can be therapeutically manipulated for the treatment of myeloid malignancies currently with dismal outcomes.


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: 2027 ( Subtotal = -$3,467 )
2027	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	000	2	10/27/2026	NON-COMPETING CONTINUATION	-$3,467
														Subtotal = -$3,467

Issue Date FY: 2026 ( Subtotal = -$24,121 )
2026	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	000	2	9/14/2026	NON-COMPETING CONTINUATION	-$24,121
														Subtotal = -$24,121

Issue Date FY: 2025 ( Subtotal = $37,482 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	001	2	7/8/2025	NON-COMPETING CONTINUATION	$564
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	000	2	4/11/2025	NON-COMPETING CONTINUATION	$36,918
														Subtotal = $37,482

Issue Date FY: 2024 ( Subtotal = $43,203 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	001	1	5/7/2024	NEW	$1,280
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	000	1	1/26/2024	NEW	$41,923
														Subtotal = $43,203

Grand Total All Awards = $53,097

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Functionally dissecting MECOM gene regulation in high-risk leukemia

Award Number: F31CA287658

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/01/2024

PERIOD OF PERFORMANCE END DATE: 05/29/2025

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