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Cancer Cell. 2019 Aug 12;36(2):194-209.e9. doi: 10.1016/j.ccell.2019.07.003.

Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation.

Author information

1
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138673, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 119077, Singapore.
2
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138673, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore.
3
Departments of Medicine and Pharmacology, Weill Cornell Medicine, New York, NY 10065, USA.
4
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
5
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138673, Singapore.
6
Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20146 Milan, Italy.
7
Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
8
Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
9
Epigenetics Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA.
10
Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
11
Division of Hematology and Medical Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, NY 10065, USA; Department of Hematology, Erasmus University Medical Center, 3015 GD Rotterdam, Netherlands.
12
Department of Hematology, Erasmus University Medical Center, 3015 GD Rotterdam, Netherlands.
13
Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada; Ontario Cancer Institute/Princess Margaret Hospital, Toronto, ON M5G 2M9, Canada.
14
Ontario Cancer Institute/Princess Margaret Hospital, Toronto, ON M5G 2M9, Canada.
15
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: abdelwao@mskcc.org.
16
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138673, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore; Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pharmacological Sciences and Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: ernesto.guccione@mssm.edu.

Abstract

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.

KEYWORDS:

AML; Arginine methylation; MDS; MS023; PRMT1; PRMT5; SF3B1; SRSF2; Splicing factor mutations; U2AF1

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