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Mutations in the RNA Splicing Factor SF3B1 Promote Tumorigenesis through MYC Stabilization

Zhaoqi Liu, Akihide Yoshimi, Jiguang Wang, Hana Cho, Stanley Chun-Wei Lee, Michelle Ki, Lillian Bitner, Timothy Chu, Harshal Shah, Bo Liu, Anthony R. Mato, Peter Ruvolo, Giulia Fabbri, Laura Pasqualucci, Omar Abdel-Wahab and Raul Rabadan
Zhaoqi Liu
1Program for Mathematical Genomics, Columbia University, New York, New York.
2Departments of Systems Biology and Biomedical Informatics, Columbia University, New York, New York.
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Akihide Yoshimi
3Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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  • ORCID record for Akihide Yoshimi
  • For correspondence: rr2579@cumc.columbia.edu yoshimia@mskcc.org
Jiguang Wang
4Division of Life Science, Department of Chemical and Biological Engineering, Center for Systems Biology and Human Health and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong SAR, China.
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Hana Cho
3Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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Stanley Chun-Wei Lee
3Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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Michelle Ki
3Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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Lillian Bitner
3Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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Timothy Chu
1Program for Mathematical Genomics, Columbia University, New York, New York.
2Departments of Systems Biology and Biomedical Informatics, Columbia University, New York, New York.
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Harshal Shah
3Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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Bo Liu
3Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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Anthony R. Mato
5Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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Peter Ruvolo
6Division of Cancer Medicine, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Giulia Fabbri
7Institute for Cancer Genetics, Columbia University, New York, New York.
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Laura Pasqualucci
7Institute for Cancer Genetics, Columbia University, New York, New York.
8Department of Pathology and Cell Biology, and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.
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Omar Abdel-Wahab
3Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
5Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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Raul Rabadan
1Program for Mathematical Genomics, Columbia University, New York, New York.
2Departments of Systems Biology and Biomedical Informatics, Columbia University, New York, New York.
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  • For correspondence: rr2579@cumc.columbia.edu yoshimia@mskcc.org
DOI: 10.1158/2159-8290.CD-19-1330 Published June 2020
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Abstract

Although mutations in the gene encoding the RNA splicing factor SF3B1 are frequent in multiple cancers, their functional effects and therapeutic dependencies are poorly understood. Here, we characterize 98 tumors and 12 isogenic cell lines harboring SF3B1 hotspot mutations, identifying hundreds of cryptic 3′ splice sites common and specific to different cancer types. Regulatory network analysis revealed that the most common SF3B1 mutation activates MYC via effects conserved across human and mouse cells. SF3B1 mutations promote decay of transcripts encoding the protein phosphatase 2A (PP2A) subunit PPP2R5A, increasing MYC S62 and BCL2 S70 phosphorylation which, in turn, promotes MYC protein stability and impair apoptosis, respectively. Genetic PPP2R5A restoration or pharmacologic PP2A activation impaired SF3B1-mutant tumorigenesis, elucidating a therapeutic approach to aberrant splicing by mutant SF3B1.

Significance: Here, we identify that mutations in SF3B1, the most commonly mutated splicing factor gene across cancers, alter splicing of a specific subunit of the PP2A serine/threonine phosphatase complex to confer post-translational MYC and BCL2 activation, which is therapeutically intervenable using an FDA-approved drug.

See related commentary by O'Connor and Narla, p. 765.

This article is highlighted in the In This Issue feature, p. 747

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Cancer Discov 2020;10:806–21

  • Received November 14, 2019.
  • Revision received February 15, 2020.
  • Accepted March 12, 2020.
  • Published first March 18, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Discovery: 10 (6)
June 2020
Volume 10, Issue 6
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Mutations in the RNA Splicing Factor SF3B1 Promote Tumorigenesis through MYC Stabilization
Zhaoqi Liu, Akihide Yoshimi, Jiguang Wang, Hana Cho, Stanley Chun-Wei Lee, Michelle Ki, Lillian Bitner, Timothy Chu, Harshal Shah, Bo Liu, Anthony R. Mato, Peter Ruvolo, Giulia Fabbri, Laura Pasqualucci, Omar Abdel-Wahab and Raul Rabadan
Cancer Discov June 1 2020 (10) (6) 806-821; DOI: 10.1158/2159-8290.CD-19-1330

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Mutations in the RNA Splicing Factor SF3B1 Promote Tumorigenesis through MYC Stabilization
Zhaoqi Liu, Akihide Yoshimi, Jiguang Wang, Hana Cho, Stanley Chun-Wei Lee, Michelle Ki, Lillian Bitner, Timothy Chu, Harshal Shah, Bo Liu, Anthony R. Mato, Peter Ruvolo, Giulia Fabbri, Laura Pasqualucci, Omar Abdel-Wahab and Raul Rabadan
Cancer Discov June 1 2020 (10) (6) 806-821; DOI: 10.1158/2159-8290.CD-19-1330
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