Investigating the Role of DNMT3A mutations in the initiation and maintenance of myeloid malignancies

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PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is an aggressive malignancy with a poor prognosis, owing in part to substantial intratumor genetic heterogeneity that allows specific subclones to evade even intensive chemotherapy. Genomic studies have identified the spectrum of frequent mutations in AML and suggest a model of sequential mutational acquisition. Early mutations are believed to confer a fitness advantage to a stem or progenitor cell enabling clonal expansion and later mutations within this expanding subclone may confer a proliferative advantage resulting in overt malignancy. AML can occur de novo, but may also develop in patients with myelodysplastic syndrome (MDS) or clonal hematopoiesis (CH). Across these disease states, DNMT3A mutations are critical initiating mutations, suggesting an opportunity to target the founding clone of these malignancies. However, targeting of DNMT3A mutations remains elusive due to a poor understanding of the mechanisms and specific role(s) of these mutations in disease. The objective of this proposal is to elucidate the specific oncogenic mechanisms of two frequent DNMT3A mutations and to define their functional contributions in the maintenance of CH, MDS, and AML. We hypothesize that genetic restoration of wildtype DNMT3A will block progression of DNMT3A-mutant CH/MDS/AML and thus that targeting the initiating DNMT3A mutations can provide a therapeutic option in myeloid disease. Moreover, a complete understanding of DNMT3A mutations will allow for the identification of targetable vulnerabilities conferred by these mutations. Specific Aim 1 will utilize inducible mouse models and ex vivo CRISPR screens to define the phenotypes, mechanisms, and conferred vulnerabilities of two DNMT3A mutations in distinct functional domains of the protein. Specific Aim 2 will use dual recombinase murine models capable of turning on and off DNMT3A mutations to determine the reversibility of DNMT3A-mutant CH and to evaluate the oncogenic dependency of DNMT3A mutations in MDS/AML. The implications of these studies will lead to novel therapeutic approaches for DNMT3A-mutant malignancies. This proposal will be conducted in the laboratory of Dr. Ross Levine (the Sponsor), who is the head of the Molecular Cancer Medicine program. The Levine lab is part of the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center (MSK), a state of the art cancer research institute. Mentorship will also be provided by Dr. Kristian Helin (the Co-Sponsor), who is the head of the Center for Epigenetics at MSK. These affiliations, along with the strong scientific and non-scientific assets of the Gerstner Sloan Kettering Graduate School, will provide a rich set of collaborative, technical, and scientific resources to execute the proposed research and career development.