Poster abstracts
Poster number 10 submitted by Maxwell Bannister
Functional characterization and therapeutic opportunities of RNA splicing factor mutants in myelodysplastic syndromes
Maxwell Bannister (Department of Pharmacology, University of Minnesota), Chan Zhou (Department of Population and Quantitative Health Sciences, University of Massachusetts ), Stanley Lee (Clinical Research Division, Fred Hutchinson Cancer Research Center), Hai Dang Nguyen (Department of Pharmacology, University of Minnesota)
Abstract:
Somatic heterozygous mutations in the RNA splicing factor (SF) genes U2AF1, SF3B1, SRSF2, and ZRSR2 occur in >50% of patients with myelodysplastic syndromes (MDS), a hematological malignancy that often progresses to secondary acute myeloid leukemia (sAML). Mutant SFs cause transcriptome-wide mis-splicing of pre-mRNA, but how this contributes to MDS pathogenesis is unclear. Moreover, targeting pre-mRNA splicing in patients carrying a SF mutation has been ineffective. My research aimed to identify new mechanistic rationales and potential targets for therapeutic development in MDS patients harboring a SF mutation. First, we found that the U2AF1S34F mutant induces the differential expression of circular RNAs (circRNAs), an emerging class of non-coding RNA formed by the ‘backsplicing’ of exons from a single pre-mRNA. Future work will characterize the disease relevance of these circRNAs. Second, our lab reported that SF-mutant cells accumulate aberrant levels of R-loops, three-stranded nucleic acid structures containing an RNA:DNA hybrid and a displaced single-stranded DNA. We hypothesized that inhibiting R-loop resolution would selectively kill SF-mutant cells. To identify potential targets, a fluorogenic high-throughput screening (HTS) assay was developed to measure RNA:DNA hybrid resolution in real-time. In parallel, we developed an in-house computational pipeline for drug sensitivity analysis and screened a small panel of compounds.
Keywords: RNA splicing, circular RNA, Myelodysplastic syndromes