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

• Published in: Cancer cell Vol. 34; no. 2; pp. 225 - 241.e8
• Main Authors: Lee, Stanley Chun-Wei, North, Khrystyna, Kim, Eunhee, Jang, Eunjung, Obeng, Esther, Lu, Sydney X., Liu, Bo, Inoue, Daichi, Yoshimi, Akihide, Ki, Michelle, Yeo, Mirae, Zhang, Xiao Jing, Kim, Min Kyung, Cho, Hana, Chung, Young Rock, Taylor, Justin, Durham, Benjamin H., Kim, Young Joon, Pastore, Alessandro, Monette, Sebastien, Palacino, James, Seiler, Michael, Buonamici, Silvia, Smith, Peter G., Ebert, Benjamin L., Bradley, Robert K., Abdel-Wahab, Omar
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13-08-2018
• Subjects: Animals; Caspase 8 - genetics; Female; Hematopoiesis; Humans; Male; Mice; Mice, Inbred C57BL; Mutation; myelodysplastic syndromes; Neoplasms - genetics; NF-kappa B - physiology; NF-κB; Phosphoproteins - genetics; RNA Splicing Factors - genetics; Serine-Arginine Splicing Factors - genetics; SF3B1; Spliceosomes; splicing; SRSF2; U2AF1; SRSF2; NF-κB; U2AF1; splicing; SF3B1; myelodysplastic syndromes
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2018.07.003

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.
[Display omitted]
•Mutations in SF3B1 and SRSF2 have a synthetic lethal interaction•Mutations in RNA splicing factors are not tolerated in a homozygous state•Mutations in SF3B1 and SRSF2 have distinct effects on pre-mRNA splicing•Both SF3B1 and SRSF2 mutations result in hyperactive NF-κB signaling
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.