Synthetic Lethal and Convergent Biological Effects of Cancer-Associated Spliceosomal Gene Mutations

Stanley Chun Wei Lee, Khrystyna North, Eunhee Kim, Eunjung Jang, Esther Obeng, Sydney X. Lu, Bo Liu, Daichi Inoue, Akihide Yoshimi, Michelle Ki, Mirae Yeo, Xiao Jing Zhang, Min Kyung Kim, Hana Cho, Young Rock Chung, Justin Taylor, Benjamin H. Durham, Young Joon Kim, Alessandro Pastore, Sebastien MonetteJames Palacino, Michael Seiler, Silvia Buonamici, Peter G. Smith, Benjamin L. Ebert, Robert K. Bradley, Omar Abdel-Wahab

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

Abstract

Mutations affecting RNA splicing factors are the most common genetic alterations in myelodysplastic syndrome (MDS) patients and occur in a mutually exclusive manner. The basis for the mutual exclusivity of these mutations and how they contribute to MDS is not well understood. Here we report that although different spliceosome gene mutations impart distinct effects on splicing, they are negatively selected for when co-expressed due to aberrant splicing and downregulation of regulators of hematopoietic stem cell survival and quiescence. In addition to this synthetic lethal interaction, mutations in the splicing factors SF3B1 and SRSF2 share convergent effects on aberrant splicing of mRNAs that promote nuclear factor κB signaling. These data identify shared consequences of splicing-factor mutations and the basis for their mutual exclusivity. Lee et al. report that SF3B1 and SRSF2 mutations elicit distinct effects on splicing and are synthetically lethal due to the cumulative impact on hematopoietic stem cell survival and quiescence. These mutations share convergent effects on promoting NF-κB signaling to drive myelodysplastic syndrome.

Original languageEnglish (US)
Pages (from-to)225-241.e8
JournalCancer Cell
Volume34
Issue number2
DOIs
StatePublished - Aug 13 2018
Externally publishedYes

Keywords

  • myelodysplastic syndromes
  • NF-κB
  • SF3B1
  • splicing
  • SRSF2
  • U2AF1

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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