Wednesday, May 15, 2024
5/15/2024
PROJECT SUMMARY: Myeloid malignancy is characterized by the acquisition of mutations in a stereotyped order with distinct patterns of cooperating mutations. Mutations in genes that alter polycomb repressive complex (PRC) function, such as BCOR, are strongly associated with acute myeloid leukemia (AML) arising from myelodysplastic syndrome (MDS). BCOR inactivating mutations disrupt non-canonical PRC1.1 complex assembly and cause the de- repression of target genes involved in leukemogenesis. We found that among patients with U2AF1 mutations, BCOR mutations were enriched exclusively in those with the S34F mutation. This proposal seeks to leverage this unique U2AF1 codon-specific co-mutation to define the mechanisms by which BCOR/PRC1.1 inactivation promotes splicing factor mutant MDS progression. I have assembled a cohort of 4,193 patients with myeloid malignancies and generated isogenic K562 cell lines and genetically engineered mice to model U2AF1S34F and BCOR co-mutation. My preliminary data indicate that U2AF1 mutation context affects the transcriptional output of BCOR/PRC1.1 inactivation and the combination of U2af1S34F and Bcor deletion in mice causes the most severe hematologic abnormalities. My central hypothesis is that U2AF1S34F enforces the conditional selection of subclonal BCOR/PRC1.1 inactivation by modulating PRC1.1 target gene expression to promote clonal expansion and worsening ineffective hematopoiesis, hallmarks of MDS progression. Aim 1 will define the clinical and genetic pathways of BCOR/PRC1.1-mediated MDS progression. Aim 2 will determine the differential effect of U2AF1S34F versus U2AF1Q157P mutations on BCOR/PRC1.1 localization, function, and target gene expression. Aim 3 will determine the impact of Bcor/PRC1.1 inactivation on U2af1S34F mutant hematopoiesis in vivo. The long-term goals of the proposed research are to gain fundamental insights into how PRC1.1 and splicing factor dysfunction interact to promote MDS progression and inform therapeutic strategies for patients. The applicant, Dr. Rahul Vedula, is an oncologist at Dana-Farber Cancer Institute (DFCI). He spends 80% of his time engaged in translational research and 20% of his time in clinical practice caring for patients with hematologic malignancies. Dr. Vedula has outlined a five-year career development plan that will enable him to meet his goal of becoming an independent translational investigator focused on myeloid disease progression. Dr. Vedula will perform the proposed research under the mentorship of Dr. Coleman Lindsley, an expert in myeloid biology and clonal hematopoiesis. Dr. Vedula has assembled a scientific advisory committee of internationally recognized experts to provide scientific and career mentorship. He will obtain additional training in the use of mouse models for hematologic malignancy research, computational biology, and biostatistics through collaborations and coursework. Dr. Vedula will conduct the proposed research at DFCI, a rich research environment with a long track-record of training successful physician-scientists.
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