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

被引：205

作者：

Fong, Jia Yi ^{[1
,2
]}

Pignata, Luca ^{[1
,3
]}

Goy, Pierre-Alexis ^{[1
,3
]}

Kawabata, Kimihito Cojin ^{[4
,5
]}

Lee, Stanley Chun-Wei ^{[6
]}

Koh, Cheryl M. ^{[1
,20
]}

Musiani, Daniele ^{[7
]}

Massignani, Enrico ^{[7
]}

Kotini, Andriana G. ^{[10
,11
]}

Penson, Alex ^{[6
]}

Wun, Cheng Mun ^{[1
]}

Shen, Yudao ^{[8
,9
]}

Schwarz, Megan ^{[10
,11
]}

Low, Diana H. P. ^{[1
]}

Rialdi, Alexander ^{[10
,11
]}

Ki, Michelle ^{[6
]}

Wollmann, Heike ^{[1
]}

Mzoughi, Slim ^{[1
]}

Gay, Florence ^{[1
]}

Thompson, Christine ^{[12
]}

Hart, Timothy ^{[12
]}

Barbash, Olena ^{[12
]}

Luciani, Genna M. ^{[13
]}

Szewczyk, Magdalena M. ^{[13
]}

Wouters, Bas J. ^{[14
,15
]}

Delwel, Ruud ^{[15
]}

Papapetrou, Eirini P. ^{[10
,11
]}

Barsyte-Lovejoy, Dalia ^{[13
]}

Arrowsmith, Cheryl H. ^{[13
,16
]}

Minden, Mark D. ^{[16
]}

Jin, Jian ^{[8
,9
]}

Melnick, Ari ^{[4
,5
]}

Bonaldi, Tiziana ^{[7
]}

Abdel-Wahab, Omar ^{[6
,17
]}

Guccione, Ernesto ^{[1
,3
,10
,11
,18
,19
]}

机构：

[1] ASTAR, Inst Mol & Cell Biol, Singapore 138673, Singapore

[2] Natl Univ Singapore, Grad Sch Integrat Sci & Engn, Singapore 119077, Singapore

[3] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore 119077, Singapore

[4] Weill Cornell Med, Dept Med, New York, NY 10065 USA

[5] Weill Cornell Med, Dept Pharmacol, New York, NY 10065 USA

[6] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[7] European Inst Oncol IRCCS, IEO, Dept Expt Oncol, I-20146 Milan, Italy

[8] Icahn Sch Med Mt Sinai, Tisch Canc Inst, Mt Sinai Ctr Therapeut Discovery, Dept Pharmacol Sci, New York, NY 10029 USA

[9] Icahn Sch Med Mt Sinai, Tisch Canc Inst, Mt Sinai Ctr Therapeut Discovery, Dept Oncol Sci, New York, NY 10029 USA

[10] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA

[11] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA

[12] GlaxoSmithKline, Epigenet Res Unit, Collegeville, PA 19426 USA

[13] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada

[14] Cornell Univ, Dept Med, Div Hematol & Med Oncol, Weill Med Coll, New York, NY 10065 USA

[15] Erasmus Univ, Dept Hematol, Med Ctr, NL-3015 GD Rotterdam, Netherlands

[16] Princess Margaret Hosp, Ontario Canc Inst, Toronto, ON M5G 2M9, Canada

[17] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, New York, NY 10065 USA

[18] Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, New York, NY 10029 USA

[19] Icahn Sch Med Mt Sinai, Mt Sinai Ctr Therapeut Discovery, New York, NY 10029 USA

[20] Silicon Therapeut, Boston, MA USA

来源：

CANCER CELL | 2019年 / 36卷 / 02期

基金：

加拿大创新基金会; 巴西圣保罗研究基金会; 英国惠康基金;

关键词：

PRE-MESSENGER-RNA; METHYLTRANSFERASE GENE EZH2; IN-VIVO; SOMATIC MUTATIONS; PHASE-SEPARATION; PRMT5; SPLICEOSOME; EXPRESSION; SF3B1; QUANTIFICATION;

D O I：

10.1016/j.ccell.2019.07.003

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：194 / +

页数：25

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