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

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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.