LAUSR

TPS7075Background: Dysregulated mRNA splicing is important in tumorigenesis and in resistance to cancer therapy. Somatic heterozygous mutations in core spliceosome genes (e.g. SF3B1, SRSF2, U2AF1) have been reported at high frequencies in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML). These mutations confer a change of function resulting in aberrant mRNA splicing that, in preclinical models, results in defects in hematopoietic cell development and myelodysplasia. Recurrent mutations in the spliceosome of patients with malignancies suggests importance in disease pathogenesis. Cells bearing splicing mutations depend on wild-type spliceosome function, suggesting the spliceosome as a therapeutic target. In vitro data indicate preferential induction of apoptosis (measured by caspase 3/7 activation) in SF3B1-mutant cells following treatment with the SF3B1 modulator H3B-8800. H3B-8800 inhibits growth in human AML cell lines, including thos...