RT Journal Article
SR Electronic
T1 Mutations in the RNA Splicing Factor SF3B1 Promote Tumorigenesis through MYC Stabilization
JF Cancer Discovery
JO Cancer Discov
FD American Association for Cancer Research
SP 806
OP 821
DO 10.1158/2159-8290.CD-19-1330
VO 10
IS 6
A1 Liu, Zhaoqi
A1 Yoshimi, Akihide
A1 Wang, Jiguang
A1 Cho, Hana
A1 Chun-Wei Lee, Stanley
A1 Ki, Michelle
A1 Bitner, Lillian
A1 Chu, Timothy
A1 Shah, Harshal
A1 Liu, Bo
A1 Mato, Anthony R.
A1 Ruvolo, Peter
A1 Fabbri, Giulia
A1 Pasqualucci, Laura
A1 Abdel-Wahab, Omar
A1 Rabadan, Raul
YR 2020
UL http://cancerdiscovery.aacrjournals.org/content/10/6/806.abstract
AB 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