Journal
BLOOD
Volume 135, Issue 13, Pages 1032-1043Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2019002894
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Funding
- National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK103854]
- NIH/National Heart, Lung, and Blood Institute [R01 HL128239]
- Department of Defense Bone Marrow Failure Research Program [W81XWH-16-1-0059]
- EvansS Foundation
- Henry & Marilyn Taub Foundation
- NIH/National Cancer Institute [P30 CA015704, K08 CA230319]
- NIH/National Cancer Institute (Genomics Shared Resources of the Fred Hutch/University of Washington Cancer Consortium)
- Conquer Cancer Foundation of the American Society of Clinical Oncology
- American Association for Cancer Research
- American Society of Hematology
- Robert Wood Johnson Foundation
- Pershing Square Sohn Cancer Research Alliance
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Genes encoding the RNA splicing factors SF3B1, SRSF2, and U2AF1 are subject to frequent missense mutations in clonal hematopoiesis and diverse neoplastic diseases. Most spliceosomal mutations affect specific hotspot residues, resulting in splicing changes that promote disease pathophysiology. However, a subset of patients carries spliceosomal mutations that affect non-hotspot residues, whose potential functional contributions to disease are unstudied. Here, we undertook a systematic characterization of diverse rare and private spliceosomal mutations to infer their likely disease relevance. We used isogenic cell lines and primary patient materials to discover that 11 of 14 studied rare and private mutations in SRSF2 and U2AF1 induced distinct splicing alterations, including partially or completely phenocopying the alterations in exon and splice site recognition induced by hotspot mutations or driving dual phenocopies that mimicked 2 co-occurring hotspot mutations. Our data suggest that many rare and private spliceosomal mutations contribute to disease pathogenesis and illustrate the utility of molecular assays to inform precision medicine by inferring the potential disease relevance of newly discovered mutations.
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