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 and
Matthew J. Walter ()
Additional contact information
Cara Lunn Shirai: Washington University School of Medicine
Brian S. White: Washington University School of Medicine
Manorama Tripathi: Washington University School of Medicine
Roberto Tapia: Washington University School of Medicine
James N. Ley: Washington University School of Medicine
Matthew Ndonwi: Washington University School of Medicine
Sanghyun Kim: Washington University School of Medicine
Jin Shao: Washington University School of Medicine
Alexa Carver: Washington University School of Medicine
Borja Saez: Massachusetts General Hospital Cancer Center
Robert S. Fulton: McDonnell Genome Institute, Washington University
Catrina Fronick: McDonnell Genome Institute, Washington University
Michelle O’Laughlin: McDonnell Genome Institute, Washington University
Chandraiah Lagisetti: SRI International
Thomas R. Webb: SRI International
Timothy A. Graubert: Massachusetts General Hospital Cancer Center
Matthew J. Walter: Washington University School of Medicine
Nature Communications, 2017, vol. 8, issue 1, 1-10
Abstract:
Abstract Somatic mutations in spliceosome genes are detectable in ∼50% 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.
Date: 2017
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14060
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DOI: 10.1038/ncomms14060
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