| Literature DB >> 31408619 |
Jia Yi Fong1, Luca Pignata2, Pierre-Alexis Goy2, Kimihito Cojin Kawabata3, Stanley Chun-Wei Lee4, Cheryl M Koh5, Daniele Musiani6, Enrico Massignani6, Andriana G Kotini7, Alex Penson4, Cheng Mun Wun5, Yudao Shen8, Megan Schwarz7, Diana Hp Low5, Alexander Rialdi7, Michelle Ki4, Heike Wollmann5, Slim Mzoughi5, Florence Gay5, Christine Thompson9, Timothy Hart9, Olena Barbash9, Genna M Luciani10, Magdalena M Szewczyk10, Bas J Wouters11, Ruud Delwel12, Eirini P Papapetrou7, Dalia Barsyte-Lovejoy10, Cheryl H Arrowsmith13, Mark D Minden14, Jian Jin8, Ari Melnick3, Tiziana Bonaldi6, Omar Abdel-Wahab15, Ernesto Guccione16.
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.Entities:
Keywords: AML; Arginine methylation; MDS; MS023; PRMT1; PRMT5; SF3B1; SRSF2; Splicing factor mutations; U2AF1
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Year: 2019 PMID： 31408619 PMCID： PMC7194031 DOI： 10.1016/j.ccell.2019.07.003
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743