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URMC / Labs / Kielkopf Lab / Projects / Molecular Actions of Prevalent U2AF1 Mutations in Myelodysplastic Syndromes (Edward P. Evans Foundat

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

GIF of 4YH8Specific 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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