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