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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 01, 2020
- Source ID
- 10.1158/2159-8290.cd-19-1330
Entities
People
- Akihide Yoshimi
- Anthony R. Mato
- Bo Liu
- Giulia Fabbri
- Hana Cho
- Harshal Shah
- Jiguang Wang
- Laura Pasqualucci
- Lillian Bitner
- Michelle Ki
- Omar Abdel-Wahab
- Peter Ruvolo
- Raúl Rabadán
- Stanley Chun-wei Lee
- Timothy Chu
- Zhaoqi Liu
Organizations
- American Society of Hematology
- Aplastic Anemia and MDS International Foundation
- Columbia University
- Edward P. Evans Foundation
- Hong Kong University of Science and Technology
- Japan Society for the Promotion of Science
- Lauri Strauss Leukemia Foundation
- Leukemia & Lymphoma Society
- Memorial Sloan Kettering Cancer Center
- National Institutes of Health
- National Science Foundation
- Pershing Square Sohn Cancer Research Alliance
- The Starr Foundation
- United States Department of Defense
- University of Texas at Austin