Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/ncomms14060
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Funding
- NIH/NHLBI [T32HL007088]
- Barnes-Jewish Hospital Foundation
- NIH/NCI SPORE in Leukemia [P50CA171963]
- NIH/NCI grant [K12CA167540, P01 CA101937]
- Clinical and Translational Award from the NIH National Center for Advancing Translational Sciences [UL1 TR000448]
- Edward P Evans Foundation
- Lottie Caroline Hardy Trust
- Leukemia and Lymphoma Society Scholar Award
- Translational Research Award
- NIH [CA140474]
- Department of Defense [BM120018]
- NCI Cancer Center Support Grant [P30CA91842]
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Somatic mutations in spliceosome genes are detectable in similar to 50% of patients with myelo-dysplastic syndromes (MDS). We hypothesize that cells harbouring spliceosome gene mutations have increased sensitivity to pharmacological perturbation of the spliceosome. We focus on mutant U2AF1 and utilize sudemycin compounds that modulate pre-mRNA splicing. We find that haematopoietic cells expressing mutant U2AF1(S34F), including primary patient cells, have an increased sensitivity to in vitro sudemycin treatment relative to controls. In vivo sudemycin treatment of U2AF1(S34F) transgenic mice alters splicing and reverts haematopoietic progenitor cell expansion induced by mutant U2AF1 expression. The splicing effects of sudemycin and U2AF1(S34F) can be cumulative in cells exposed to both perturbations-drug and mutation-compared with cells exposed to either alone. These cumulative effects may result in downstream phenotypic consequences in sudemycin-treated mutant cells. Taken together, these data suggest a potential for treating haematological cancers harbouring U2AF1 mutations with pre-mRNA splicing modulators like sudemycins.
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