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

Jia Yi Fong, Luca Pignata, Pierre Alexis Goy, Kimihito Cojin Kawabata, Stanley Chun Wei Lee, Cheryl M. Koh, Daniele Musiani, Enrico Massignani, Andriana G. Kotini, Alex Penson, Cheng Mun Wun, Y. Shen, M. Schwarz, Diana HP Low, Alexander Rialdi, Michelle Ki, H. Wollmann, Slim Mzoughi, Florence Gay, Christine ThompsonTimothy Hart, O. Barbash, Genna M. Luciani, Magdalena M. Szewczyk, B. J. Wouters, Ruud Delwel, Eirini P. Papapetrou, D. Barsyte-Lovejoy, Cheryl H. Arrowsmith, Mark D. Minden, Jian Jin, Ari Melnick, Tiziana Bonaldi, Omar Abdel-Wahab, Ernesto Guccione

Research output: Contribution to journalArticlepeer-review

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. Fong et al. show that spliceosomal mutant leukemias are preferentially sensitive to inhibition of protein arginine methyltransferases (PRMTs), that RNA-binding proteins are enriched among substrates of PRMT5 and type I PRMTs, and that combined PRMT5 and type I PRMT inhibition synergistically kill these leukemia cells.

Original languageEnglish
Pages (from-to)194-209.e9
JournalCancer Cell
Volume36
Issue number2
DOIs
Publication statusPublished - Aug 12 2019

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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