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Cancer Cell. 2018 Aug 13;34(2):225-241.e8. doi: 10.1016/j.ccell.2018.07.003.

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

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, Zuckerman 701, 408 East 69(th) Street, New York, NY 10065, USA.
2
Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Mailstop: M1-B514, Seattle, WA 98109-1024, USA; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Genome Sciences, University of Washington, Seattle, WA, USA.
3
School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
4
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
5
Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, The Rockefeller University, New York, NY, USA.
6
H3 Biomedicine, Cambridge, MA, USA.
7
Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Mailstop: M1-B514, Seattle, WA 98109-1024, USA; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Genome Sciences, University of Washington, Seattle, WA, USA. Electronic address: rbradley@fredhutch.org.
8
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, Zuckerman 701, 408 East 69(th) Street, New York, NY 10065, USA; Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: abdelwao@mskcc.org.

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.

KEYWORDS:

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

PMID:
30107174
PMCID:
PMC6373472
[Available on 2019-08-13]
DOI:
10.1016/j.ccell.2018.07.003

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