RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis

Nat Commun. 2021 May 18;12(1):2901. doi: 10.1038/s41467-021-23186-w.

Abstract

Proliferative chronic myelomonocytic leukemia (pCMML), an aggressive CMML subtype, is associated with dismal outcomes. RAS pathway mutations, mainly NRASG12D, define the pCMML phenotype as demonstrated by our exome sequencing, progenitor colony assays and a Vav-Cre-NrasG12D mouse model. Further, these mutations promote CMML transformation to acute myeloid leukemia. Using a multiomics platform and biochemical and molecular studies we show that in pCMML RAS pathway mutations are associated with a unique gene expression profile enriched in mitotic kinases such as polo-like kinase 1 (PLK1). PLK1 transcript levels are shown to be regulated by an unmutated lysine methyl-transferase (KMT2A) resulting in increased promoter monomethylation of lysine 4 of histone 3. Pharmacologic inhibition of PLK1 in RAS mutant patient-derived xenografts, demonstrates the utility of personalized biomarker-driven therapeutics in pCMML.

Publication types

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

MeSH terms

  • Animals
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Exome Sequencing / methods
  • GTP Phosphohydrolases / genetics*
  • GTP Phosphohydrolases / metabolism
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Leukemic
  • Histone-Lysine N-Methyltransferase / genetics*
  • Histone-Lysine N-Methyltransferase / metabolism
  • Kaplan-Meier Estimate
  • Leukemia, Myelomonocytic, Chronic / genetics*
  • Leukemia, Myelomonocytic, Chronic / metabolism
  • Leukemia, Myelomonocytic, Chronic / therapy
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mutation*
  • Myeloid-Lymphoid Leukemia Protein / genetics*
  • Myeloid-Lymphoid Leukemia Protein / metabolism
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Signal Transduction / genetics
  • Stem Cell Transplantation / methods
  • Transplantation, Homologous
  • Xenograft Model Antitumor Assays / methods

Substances

  • Cell Cycle Proteins
  • KMT2A protein, human
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • Protein Serine-Threonine Kinases
  • polo-like kinase 1
  • GTP Phosphohydrolases
  • NRAS protein, human