Mutations in the RNA splicing factor SF3B1 promote tumorigenesis through MYC stabilization Journal Article

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.
Article Title: Mutations in the RNA splicing factor SF3B1 promote tumorigenesis through MYC stabilization
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. ©2020 American Association for Cancer Research.
Journal Title: Cancer Discovery
Volume: 10
Issue: 6
ISSN: 2159-8274
Publisher: American Association for Cancer Research  
Date Published: 2020-06-01
Start Page: 806
End Page: 821
Language: English
DOI: 10.1158/2159-8290.Cd-19-1330
PUBMED: 32188705
PROVIDER: scopus
Notes: Article -- Export Date: 1 July 2020 -- Source: Scopus
Citation Impact
MSK Authors
  1. Stanley Chun-Wei Lee
    43 Lee
  2. Ha Na   Cho
    16 Cho
  3. Akihide   Yoshimi
    34 Yoshimi
  4. Bo Liu
    15 Liu
  5. Anthony R Mato
    123 Mato
  6. Michelle Carmen Ki
    16 Ki
  7. Lillian Elizabeth Bitner
    12 Bitner
  8. Harshal R Shah
    2 Shah