Molecular Actions of Prevalent U2AF1 Mutations in Myelodysplastic Syndromes (Edward P. Evans Foundation)

Specific mutations in the U2AF1 proto-oncogene, which encodes the U2AF35 protein, are prevalent among patients with hematological malignancies, including 10-12% of patients with myelodysplastic syndrome (MDS) without ring sideroblasts and 8-11% of patients with chronic myelomonocytic leukemia (CMML). The major goals of this project are to investigate the molecular and structural mechanisms for altered pre-mRNA splicing in MDS patients carrying somatic mutations of the U2AF1 pre-mRNA splicing factor. Specifically, we will: (i) Determine the effect of prevalent U2AF1 mutations on U2AF35 binding affected pre-mRNA splice sites of MDS patient samples, focusing on known proto-oncogenic transcripts; (ii) Determine structures of the U2AF35 protein bound to splice RNA and evaluate the locations of the mutated residues; (iii) Screen chemical libraries for inhibitors of mutant U2AF35 complexes. The results of these aims provide a foundation for understanding the molecular and structural roles of U2AF1 in aberrant pre-mRNA splicing that leads to MDS and other malignancies. This approach will also identify selective modulators of U2AF1 mutants that can provide potential long-term therapies in a new genomic age of Precision Medicine.

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