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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Catalysis
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Ethylenediamines / pharmacokinetics
  • Ethylenediamines / pharmacology*
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • Humans
  • K562 Cells
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Protein-Arginine N-Methyltransferases / antagonists & inhibitors*
  • Protein-Arginine N-Methyltransferases / genetics
  • Protein-Arginine N-Methyltransferases / metabolism
  • Pyrroles / pharmacokinetics
  • Pyrroles / pharmacology*
  • RNA Splicing / drug effects*
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism*
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / metabolism
  • THP-1 Cells
  • Tumor Cells, Cultured
  • U937 Cells
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Ethylenediamines
  • MS023 compound
  • Pyrroles
  • RNA, Neoplasm
  • Repressor Proteins
  • PRMT1 protein, human
  • PRMT5 protein, human
  • Protein-Arginine N-Methyltransferases