Although mutations in 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 PP2A phosphatase subunit PPP2R5A, increasing c-MYC S62 and BCL2 S70 phosphorylation which, in turn, promote 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.
Mutations in the RNA splicing factor SF3B1 promote tumorigenesis through MYC stabilization
Pasqualucci, Laura;
2020
Abstract
Although mutations in 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 PP2A phosphatase subunit PPP2R5A, increasing c-MYC S62 and BCL2 S70 phosphorylation which, in turn, promote 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
