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

Ryan M. Carr, Denis Vorobyev, Terra Lasho, David L. Marks, Ezequiel J. Tolosa, Alexis Vedder, Luciana L. Almada, Andrey Yurcheko, Ismael Padioleau, Bonnie Alver, Giacomo Coltro, Moritz Binder, Stephanie L. Safgren, Isaac Horn, Xiaona You, Eric Solary, Maria E. Balasis, Kurt Berger, James Hiebert, Thomas WitzigAjinkya Buradkar, Temeida Graf, Peter Valent, Abhishek A. Mangaonkar, Keith D. Robertson, Matthew T. Howard, Scott H. Kaufmann, Christopher Pin, Martin E. Fernandez-Zapico, Klaus Geissler, Nathalie Droin, Eric Padron, Jing Zhang, Sergey Nikolaev, Mrinal M. Patnaik

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number2901
JournalNature communications
Issue number1
StatePublished - Dec 1 2021

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)


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