PRMT5 methylome profiling uncovers a direct link to splicing regulation in acute myeloid leukemia

Nat Struct Mol Biol. 2019 Nov;26(11):999-1012. doi: 10.1038/s41594-019-0313-z. Epub 2019 Oct 14.

Abstract

Protein arginine methyltransferase 5 (PRMT5) has emerged as a promising cancer drug target, and three PRMT5 inhibitors are currently in clinical trials for multiple malignancies. In this study, we investigated the role of PRMT5 in human acute myeloid leukemia (AML). Using an enzymatic dead version of PRMT5 and a PRMT5-specific inhibitor, we demonstrated the requirement of the catalytic activity of PRMT5 for the survival of AML cells. We then identified PRMT5 substrates using multiplexed quantitative proteomics and investigated their role in the survival of AML cells. We found that the function of the splicing regulator SRSF1 relies on its methylation by PRMT5 and that loss of PRMT5 leads to changes in alternative splicing of multiple essential genes. Our study proposes a mechanism for the requirement of PRMT5 for leukemia cell survival and provides potential biomarkers for the treatment response to PRMT5 inhibitors.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Arginine / analogs & derivatives
  • Arginine / biosynthesis
  • Arginine / metabolism
  • Catalysis
  • Cell Line, Tumor
  • Cell Survival
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation, Leukemic
  • Humans
  • Leukemia, Myeloid, Acute / enzymology*
  • Leukemia, Myeloid, Acute / genetics
  • Methylation
  • Mice
  • Molecular Targeted Therapy
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / metabolism
  • Neoplasm Proteins / physiology*
  • Oncogene Proteins, Fusion / genetics
  • Protein Processing, Post-Translational* / genetics
  • Protein-Arginine N-Methyltransferases / antagonists & inhibitors
  • Protein-Arginine N-Methyltransferases / deficiency
  • Protein-Arginine N-Methyltransferases / physiology*
  • Proteomics
  • RNA Splicing*
  • Serine-Arginine Splicing Factors / metabolism

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • MLL-AF9 fusion protein, human
  • MLL-AF9 fusion protein, mouse
  • Neoplasm Proteins
  • Oncogene Proteins, Fusion
  • SRSF1 protein, human
  • dimethylarginine
  • Myeloid-Lymphoid Leukemia Protein
  • Serine-Arginine Splicing Factors
  • Arginine
  • PRMT5 protein, human
  • Protein-Arginine N-Methyltransferases