期刊
CANCER CELL
卷 36, 期 2, 页码 194-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2019.07.003
关键词
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资金
- AGS fellowship
- AGA-SINGA (Singapore Graduate Award) [NMRC/OFIRG/0032/2017, NRF-CRP17-2017-06]
- RNA Biology Center at the Cancer Science Institute of Singapore, NUS under Singapore Ministry of Education's AcRF [MOE2014-T3-1-006]
- Leukemia and Lymphoma Society
- NIH/NHLBI [R01 HL128239]
- NIH/NCI [1 R01 CA201247-01A1]
- US Department of Defense Bone Marrow Failure Research Program [W81XWH-12-1-0041]
- Cycle For Survival
- Edward P. Evans Foundation
- Henry AMP
- Marilyn Taub Foundation
- Pershing Square Sohn Foundation
- Starr Foundation [I8-A8-075, I9-A9-059]
- Leukemia and Lymphoma Society of Canada
- AbbVie
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada
- Innovative Medicines Initiative (EU/EFPIA) (ULTRADD) [115766]
- Janssen
- Merck
- Novartis Pharma AG
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Sao Paulo Research Foundation FAPESP
- Takeda
- Wellcome Trust
- Italian Ministry of Health [GR-2011-02347880]
- Epigen Flagship project (CNR)
- Italian Association for Cancer Research [IG-2018-21834]
- Fondazione Umberto Veronesi (FUV)
- Fondazione Istituto Europeo di Oncologia (FIEO)
- NIH [T32 CA078207]
- US NIH [R01GM122749]
Cancer-associated mutations in genes encoding RNA splicing factors (SFs) commonly occur in leukemias, as well as in a variety of solid tumors, and confer dependence on wild-type splicing. These observations have led to clinical efforts to directly inhibit the spliceosome in patients with refractory leukemias. Here, we identify that inhibiting symmetric or asymmetric dimethylation of arginine, mediated by PRMT5 and type I protein arginine methyltransferases (PRMTs), respectively, reduces splicing fidelity and results in preferential killing of SF-mutant leukemias over wild-type counterparts. These data identify genetic subsets of cancer most likely to respond to PRMT inhibition, synergistic effects of combined PRMT5 and type I PRMT inhibition, and a mechanistic basis for the therapeutic efficacy of PRMT inhibition in cancer.
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