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RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis
Nature Communications
  • Ryan M. Carr, Mayo Clinic
  • Denis Vorobyev, Institut de Cancerologie Gustave Roussy
  • Terra Lasho, Mayo Clinic
  • David L. Marks, Mayo Clinic
  • Ezequiel J. Tolosa, Mayo Clinic
  • Alexis Vedder, Moffitt Cancer Center
  • Luciana L. Almada, Mayo Clinic
  • Andrey Yurcheko, Institut de Cancerologie Gustave Roussy
  • Ismael Padioleau, Institut de Cancerologie Gustave Roussy
  • Bonnie Alver, Mayo Clinic
  • Giacomo Coltro, Mayo Clinic
  • Moritz Binder, Mayo Clinic
  • Stephanie L. Safgren, Mayo Clinic
  • Isaac Horn, Mayo Clinic
  • Xiaona You, McArdle Laboratory for Cancer Research
  • Eric Solary, Institut de Cancerologie Gustave Roussy
  • Maria E. Balasis, Moffitt Cancer Center
  • Kurt Berger, Lawson Health Research Institute
  • James Hiebert, Mayo Clinic
  • Thomas Witzig, Mayo Clinic
  • Ajinkya Buradkar, Mayo Clinic
  • Temeida Graf, Medizinische Universität Wien
  • Peter Valent, Medizinische Universität Wien
  • Abhishek A. Mangaonkar, Mayo Clinic
  • Keith D. Robertson, Mayo Clinic
  • Matthew T. Howard, Mayo Clinic
  • Scott H. Kaufmann, Mayo Clinic
  • Christopher Pin, Lawson Health Research Institute
  • Martin E. Fernandez-Zapico, Mayo Clinic
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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.

Citation Information
Ryan M. Carr, Denis Vorobyev, Terra Lasho, David L. Marks, et al.. "RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis" Nature Communications Vol. 12 Iss. 1 (2021)
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