Mutant U2AF1-expressing cells are sensitive to pharmacological modulation of the spliceosome

Cara Lunn Shirai, Brian S. White, Manorama Tripathi, Roberto Tapia, James N. Ley, Matthew Ndonwi, Sanghyun Kim, Jin Shao, Alexa Carver, Borja Saez, Robert S. Fulton, Catrina Fronick, Michelle O'Laughlin, Chandraiah Lagisetti, Thomas R. Webb, Timothy A. Graubert, Matthew J. Walter

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66 Scopus citations

Abstract

Somatic mutations in spliceosome genes are detectable in â1/450% of patients with myelodysplastic 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.

Original languageEnglish
Article number14060
JournalNature communications
Volume8
DOIs
StatePublished - Jan 9 2017

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