Mutations in the RNA Splicing Factor SF3B1 Promote Tumorigenesis through MYC Stabilization
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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
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PP2A-B56α inhibition drives malignant transformation of human cells and promotes malignant growth.
“Through loss-of-function studies it has been shown that PP2A-B56α inhibition drives malignant transformation of human cells, as well promotes malignant growth6,8.”
From Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A (2023) · cites this paper as [8]
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Research works printed but not linked: 1
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Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A
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“The data show that the CIP2A(1-560) residues cross-linked to B56α are located primarily in the N-terminal head domain (K18, K21, E23, E34, K40) with an additional residue at the C-terminus (K490) (Fig.”
BackgroundMethodInfluentialSun, L., Liu, Y., Guo, X., Cui, T., Wu, C., Tao, J., Cheng, C., Chu, Q., Ji, C., Li, X., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-49573-7 · Cited by 18 · see citing works
Self-citation
- Authors
- Liu, Z., Yoshimi, A., Wang, J., Cho, H., Chun-Wei Lee, S., Ki, M., Bitner, L., Chu, T., Shah, H., Liu, B., Mato, A. R., Ruvolo, P., Fabbri, G., Pasqualucci, L., Abdel-Wahab, O., & Rabadan, R.
- Affiliations
- Columbia University (US)
- Memorial Sloan Kettering Cancer Center (US)
- Hong Kong University of Science and Technology (HK)
- 3Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
- The University of Texas MD Anderson Cancer Center (US)
- Herbert Irving Comprehensive Cancer Center (US)
- 1Program for Mathematical Genomics, Columbia University, New York, New York.
- Corresponding author
- Yoshimi, Akihide
- ORCID
- Venue
- Cancer Discovery
- Published
- 2020-06-01
- Volume
- 10
- Issue
- 6
- Pages
- 806-821
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC8188517
- OpenAlex
- W3011565525
- Cited by
- 118
- References
- 44
- Citations by year
- 2026: 10 · 2025: 20 · 2024: 16 · 2023: 19 · 2022: 22 · 2021: 22 · 2020: 9
- FWCI
- 5.83
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- NIH (P01CA087497, R01 CA185486, R01 CA179044, U54 CA193313, U54 209997)
- Aplastic Anemia
- MDS International Foundation
- Lauri Strauss Leukemia Foundation
- JSPS
- Leukaemia and Lymphoma
- NIH NCI (K99 CA218896)
- American Society of Hematology
- NIH NHLBI (R01 HL128239)
- Department of Defense (W81XWH-16-1-0059)
- Starr Foundation (I8-A8-075)
- Henry & Marilyn Taub Foundation
- Edward P. Evans Foundation
- Leukemia and Lymphoma Society
- Pershing Square Sohn Cancer Research Alliance
- NSF SU2C V Foundation (PHY-1545805)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- SF3B1 mutation, RNA splicing, cryptic 3' splice site, MYC stabilization, protein phosphatase 2A, carcinogenesis, apoptosis, therapeutic target
- MeSH terms
- RNA Splicing Factors, Cell Transformation, Neoplastic, Humans, Neoplasms, Phosphoproteins, Carcinogenesis
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