期刊
CANCER CELL
卷 34, 期 2, 页码 225-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2018.07.003
关键词
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资金
- Leukemia and Lymphoma Society
- NCI [K99 CA218896]
- Aplastic Anemia and MDS International Foundation
- Lauri Strauss Leukemia Foundation
- US Dept. of Defense Bone Marrow Failure Research Program grant [W81XWH-12-1-0041]
- National Research Foundation of Korea (NRF) - Korean Government (Young Researcher Program) [NRF-2017R1C1B2001991]
- Settlement Research Fund of UNIST (Ulsan National Institute of Science and Technology) [1.160104.01]
- NRF grant (the Individual Research in Basic Science and Engineering program) [NRF-2017R1C1B2001991]
- American Society of Hematology
- Edward P. Evans Foundation
- Taub Foundation [R01 HL128239]
- Ellison Medical Foundation [AG-NS-1030-13, R01 DK103854]
- Starr Foundation [I8-A8-075, I9-A9-059]
- Pershing Square Sohn Foundation
- MSK Cancer Center [P30 CA008748]
Mutations affecting RNA splicing factors are the most common genetic alterations in myelodysplastic syndrome (MDS) patients and occur in a mutually exclusive manner. The basis for the mutual exclusivity of these mutations and how they contribute to MDSis not well understood. Here we report that although different spliceosome gene mutations impart distinct effects on splicing, they are negatively selected for when co-expressed due to aberrant splicing and downregulation of regulators of hematopoietic stem cell survival and quiescence. In addition to this synthetic lethal interaction, mutations in the splicing factors SF3B1 and SRSF2 shareconvergent effects on aberrant splicing of mRNAs that promote nuclear factor kB signaling. These data identify shared consequences of splicing-factor mutations and the basis for their mutual exclusivity.
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