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Elucidating the Non-canonical Roles of MCL-1 in Acute Myeloid Leukemia

Award Number: F31CA318247
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/11/2026
PERIOD OF PERFORMANCE END DATE: 08/10/2029

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Elucidating the Non-canonical Roles of MCL-1 in Acute Myeloid Leukemia - PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is a common and aggressive hematologic malignancy with high relapse rates. Relapse is driven by chemotherapy-resistant leukemia stem cells (LSCs), and despite extensive efforts to improve treatments, the survival rate for relapsed AML is just 10%. These clinical challenges underscore an urgent need to define core mechanisms that sustain LSC survival and identify actionable vulnerabilities. Overexpression of the pro-survival protein MCL-1 is associated with poor prognosis and drug resistance in LSCs. While MCL-1 is best known for inhibiting apoptosis, its non-apoptotic functions remain poorly understood in AML and may represent therapeutic vulnerabilities. We recently discovered that MCL-1 regulates lipid metabolism by directly binding ACSL1 to promote long-chain fatty acid oxidation (FAO). Given that FAO supports LSC self- renewal and stress resistance, I hypothesize that MCL-1 confers metabolic protection in AML, independent of its well-known anti-apoptotic role. My proposed project aims to elucidate MCL-1’s non-apoptotic functions in AML metabolism and LSC maintenance. To isolate these roles, I will perturb MCL-1 in four genetically defined AML subtypes lacking BAX and BAK, rendering cells apoptosis-deficient. Preliminary data reveal that Mcl1/Bax/Bak triple knockout (TKO) AML exhibits subtype-specific growth defects compared to Bax/Bak double knockout (DKO) controls, revealing apoptosis-independent roles for MCL-1 in LSC self-renewal. I will compare TKO and DKO cells for metabolic profiles, differentiation states, and transcriptional signatures to define MCL-1-regulated programs apart from apoptosis. The second aim of my project will dissect the role of the MCL-1/ACSL1 axis in AML and achieve a mechanistic understanding of these roles. I will leverage Acsl1 conditional knockout AML models and ACSL1 mutants that modulate the MCL-1 binding interface. Using these tools, I will assess the interaction’s role in growth, FAO, self-renewal, and resistance to ferroptosis and apoptosis. Preliminary studies show that ACSL1 resists ferroptosis in AML cells, and that ACSL1 mutants which enhance or disrupt the MCL- 1/ACSL1 interaction bidirectionally alters lipid utilization. By delineating apoptosis-independent functions of MCL- 1, this work will uncover core mechanisms of AML maintenance and inform next-generation therapies to eradicate LSCs. The Opferman laboratory at St. Jude Children’s Research Hospital, with its deep expertise in MCL-1 biology, apoptosis, and hematopoietic stem cell metabolism, provides an exceptional environment to accomplish this project. Dr. Opferman and St. Jude colleagues fully support my training goals of learning techniques in cancer cell biology, designing rigorous and well-rounded experiments, scientific communication of my results, and mentorship. Core Facilities and Academic Programs Office resources will further enable rigorous execution and dissemination of my findings. Combined with support from the Ruth L. Kirschtein Predoctoral Individual National Research Service Award (F31), this training will provide an excellent launching pad toward my goal of becoming an independent academic investigator.


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: 2026 ( Subtotal = $49,114 )
2026	2026	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL # 1500	MEMPHIS	TN	38105	SHELBY	USA	Cancer Research Manpower	001	1	8/11/2026	NEW	$0
2026	2026	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL # 1500	MEMPHIS	TN	38105	SHELBY	USA	Cancer Research Manpower	000	1	8/11/2026	NEW	$49,114
														Subtotal = $49,114

Grand Total All Awards = $49,114

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Elucidating the Non-canonical Roles of MCL-1 in Acute Myeloid Leukemia

Award Number: F31CA318247

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/11/2026

PERIOD OF PERFORMANCE END DATE: 08/10/2029

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