RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34006870.
- Also identified by DOI 10.1038/s41467-021-23186-w and PMC identifier 8131698.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Proliferative chronic myelomonocytic leukemia (pCMML), an aggressive CMML subtype, is associated with dismal outcomes. RAS pathway mutations, mainly NRAS<sup>G12D</sup>, define the pCMML phenotype as demonstrated by our exome sequencing, progenitor colony assays and a Vav-Cre-Nras<sup>G12D</sup> 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.
Medical subject headings
- Cell Cycle Proteins
- GTP Phosphohydrolases
- Histone-Lysine N-Methyltransferase
- Leukemia, Myelomonocytic, Chronic
- Membrane Proteins
- Mutation
- Myeloid-Lymphoid Leukemia Protein
- Protein Serine-Threonine Kinases
- Proto-Oncogene Proteins