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Characterizing the role of MARCH5 in apoptosis regulation in acute myeloid leukemia

Award Number: R00CA263161
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Characterizing the role of MARCH5 in apoptosis regulation in acute myeloid leukemia - Project Summary Acute myeloid leukemia (AML) remains a devastating illness, with a clear need for the development of novel anti-leukemic therapy. Inhibition of anti-apoptotic BCL2 family proteins to directly stimulate apoptosis provides a feasible therapeutic strategy for treating AML. Venetoclax, a BCL2-specific inhibitor, has exhibited promising anti-leukemic effect in a subset of patients with AML. However, resistance to venetoclax can develop. Therefore, identification of other synergistic targets attacking the apoptosis defense system is needed to enhance the efficacy of anti-BCL2 therapy in AML. Integrating functional genomics and xenograft models, I developed an in vivo CRISPR-Cas9 screen approach to identify MARCH5, a RING-type ubiquitin E3 ligase, as an essential gene for AML cell growth. My preliminary studies showed that MARCH5 is a critical regulator of apoptosis in AML cells. MARCH5-depleted AML cells display increased apoptotic cell death and enhanced sensitivity to venetoclax, suggesting that MARCH5 can serve as a potential therapeutic target for AML. The goal of this proposal is to evaluate the translational potential of targeting MARCH5 as an AML therapy, and investigate the mechanism of action of MARCH5 protein and its related network to provide biological insights for the development of therapeutic strategies targeting MARCH5. The Specific Aims are: (1) Determine the domains of the MARCH5 protein critical for preventing apoptosis in AML; (2) Evaluate the therapeutic potential of MARCH5 inhibition in preclinical models of AML; and (3) Identify the key regulatory proteins critical for MARCH5-mediated apoptosis regulation. This study will deepen our understanding of the apoptosis regulation and its clinical application in AML, uncover novel therapeutic opportunities for targeting MARCH5 and AML, and provide a synergistic approach to enhance the efficacy of venetoclax in AML and potentially other malignancies. I am a postdoctoral research fellow in the laboratory of Dr. Kimberly Stegmaier at the Department of Pediatric Oncology at Dana-Farber Cancer Institute (DFCI). My current research focuses on identification and characterization novel dependencies in acute leukemia, and the application of these knowledge to the development of novel therapeutic approaches. My long-term career goal is to establish a research program focusing on understanding the molecular mechanisms of leukemogenesis and leukemia vulnerabilities, with a strong commitment to translate basic scientific discoveries into the clinic. The proposed research will form a solid platform from which I can establish my own research group by the end of the K99 Award period. I have developed a focused training plan to accomplish my goal: (1) expand my scientific knowledge and vision; (2) sharpen my critical thinking and technical skills; and (3) develop and strengthen my professional skills. With the mentorship of Dr. Kimberly Stegmaier, deep support from my scientific advisory committee, and rich resource and collaborative environment offered by DFCI and the Harvard community, I will be well prepared for the transition into the independence.


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 = $248,979 )
2025	2025	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Cancer Treatment Research	000	4	3/14/2025	NON-COMPETING CONTINUATION	$224,082
2025	2025	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Cancer Treatment Research	001	4	5/22/2025	NON-COMPETING CONTINUATION	$24,897
														Subtotal = $248,979

Issue Date FY: 2024 ( Subtotal = $248,983 )
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Cancer Treatment Research	000	3	4/10/2024	EXTENSION WITH OR WITHOUT FUNDS	$248,983
														Subtotal = $248,983

Grand Total All Awards = $497,962

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Characterizing the role of MARCH5 in apoptosis regulation in acute myeloid leukemia

Award Number: R00CA263161

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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