Oncogenic <i>SF3B1</i> mutations alter the splicing of mRNA noncoding regions to induce a novel therapeutic vulnerability
Abstract
Abstract Oncogenic mutations of SF3B1 are common in myeloid cancers, chronic lymphocytic leukemia (CLL), and select solid tumors. Their mechanistic basis for promoting oncogenesis has been investigated in detail, with the stereotyped missplicing of messenger RNA (mRNA) protein coding sequences most intensively studied. These changes, in genes such as MAP3K7, BRD9, and ABCB7, typically lead to loss of function, thus contributing to cancer pathogenesis. Here, we systematically analyzed the impact of mutant SF3B1 on noncoding regions of mRNA transcripts across disease types, in both cell lines and primary patient specimens. This identified numerous novel and highly reproducible splicing alterations in such regions. Studies of a target gene, DCAF16, revealed multiple complex mutation-induced alterations in its 5′ and 3′ untranslated regions (UTRs). Remarkably, these were mechanistically associated with increased DCAF16 protein levels in SF3B1-mutant cells, representing, to our knowledge, the first time that oncogenic SF3B1 has been found to increase levels of a target protein in a gain-of-function manner. DCAF16 is a substrate recognition adapter for the DDB1/CUL4 E3 ubiquitin ligase complex. Novel protein degrader small molecules that coopt DCAF16 to degrade BRD4 as a neosubstrate demonstrated preferential selectivity for SF3B1-mutant cancers and CLL primary patient specimens due to increased DCAF16 protein levels. In turn, this reveals the therapeutic relevance of mutant SF3B1 dysregulation of transcript UTRs and uncovers a novel strategy for the treatment of these important neoplasms.
Article Details
Authors (39)
Michal Sekrecki
1Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
Agata Sekrecka
1Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
Rohan R. Lattupally
1Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
Kenny Le
1Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
Xiaokang Jin
Department of Chemistry
Chen Mozes
2Department of Chemistry, Northwestern University, Chicago, IL
Brendan G. Dwyer
Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine
Zhe Zhuang
Department of Chemical and Systems Biology, ChEM-H and Stanford Cancer Institute, Stanford Medical School
Bryan A. Romero
Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine
Jose M. B. Pineda
1Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
Xunhong Cao
1Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
Linh Nguyen
Vicky Chen
Crystal M. Zhou
1Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
Jared A. Wallace
1Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
Kailee Tanaka
Charu Tiwari
1Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
Austin Gabel
6Department of Genome Sciences and Medical Scientist Training Program, University of Washington, Seattle, WA
Won Jun Kim
Robert F. Stanley
7Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
Salima Benbarche
Molecular Pharmacology Program, Sloan Kettering Institute
Jaspreet Thind
Department of Cell Biology and Genetics, Texas A&M University Health Science Center
Abhinaya Muruganandham
8Department of Cell Biology and Genetics, Texas A&M University Health Science Center, Bryan, TX
Tian Yi Zhang
1Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
Peter L. Greenberg
1Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
Jason R. Gotlib
1Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
Gabriel Mannis
1Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
William E. Shomali
1Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
Giselle Salmasi
1Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
Calvin Kuo
Tait Shanafelt
1Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
Irtisha Singh
Interdisiplinary program in Genetics and Genomics, College of Agriculture and Life Sciences, Texas A&M University
Daichi Inoue
Finn K. Hansen
11Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, Bonn, Germany
Nathanael S. Gray
Capucine van Rechem
4Department of Pathology, Stanford University School of Medicine, Stanford, CA
Bita Fakhri
1Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
Xiaoyu Zhang
Sydney X. Lu
1Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA