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

Author

Listed:
  • Ryan M. Carr

    (Department of Internal Medicine
    Division of Oncology Research)

  • Denis Vorobyev

    (INSERM U981, Gustave Roussy Cancer Center)

  • Terra Lasho

    (Department of Internal Medicine)

  • David L. Marks

    (Division of Oncology Research)

  • Ezequiel J. Tolosa

    (Division of Oncology Research)

  • Alexis Vedder

    (Moffitt Cancer Center)

  • Luciana L. Almada

    (Division of Oncology Research)

  • Andrey Yurcheko

    (INSERM U981, Gustave Roussy Cancer Center)

  • Ismael Padioleau

    (INSERM U981, Gustave Roussy Cancer Center)

  • Bonnie Alver

    (Molecular Pharmacology and Experimental Therapeutics)

  • Giacomo Coltro

    (Department of Internal Medicine)

  • Moritz Binder

    (Department of Internal Medicine)

  • Stephanie L. Safgren

    (Division of Oncology Research)

  • Isaac Horn

    (Division of Oncology Research)

  • Xiaona You

    (University of Wisconsin-Madison)

  • Eric Solary

    (Gustave Roussy Cancer Center)

  • Maria E. Balasis

    (Moffitt Cancer Center)

  • Kurt Berger

    (Lawson Health Research Institute University of Western Ontario)

  • James Hiebert

    (Department of Internal Medicine)

  • Thomas Witzig

    (Department of Internal Medicine)

  • Ajinkya Buradkar

    (Department of Internal Medicine)

  • Temeida Graf

    (Medical University of Vienna)

  • Peter Valent

    (Medical University of Vienna
    Ludwig Boltzmann Institute for Hematology and Hemostaseology, Medical University of Vienna)

  • Abhishek A. Mangaonkar

    (Department of Internal Medicine)

  • Keith D. Robertson

    (Molecular Pharmacology and Experimental Therapeutics)

  • Matthew T. Howard

    (Department of Laboratory Medicine and Pathology)

  • Scott H. Kaufmann

    (Department of Internal Medicine)

  • Christopher Pin

    (Lawson Health Research Institute University of Western Ontario)

  • Martin E. Fernandez-Zapico

    (Division of Oncology Research)

  • Klaus Geissler

    (Sigmund Freud University Vienna)

  • Nathalie Droin

    (Gustave Roussy Cancer Center)

  • Eric Padron

    (Moffitt Cancer Center)

  • Jing Zhang

    (University of Wisconsin-Madison)

  • Sergey Nikolaev

    (INSERM U981, Gustave Roussy Cancer Center)

  • Mrinal M. Patnaik

    (Department of Internal Medicine)

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.

Suggested Citation

  • 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 Bind, 2021. "RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23186-w
    DOI: 10.1038/s41467-021-23186-w
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    Cited by:

    1. Alicia Villatoro & Vincent Cuminetti & Aurora Bernal & Carlos Torroja & Itziar Cossío & Alberto Benguría & Marc Ferré & Joanna Konieczny & Enrique Vázquez & Andrea Rubio & Peter Utnes & Almudena Tello, 2023. "Endogenous IL-1 receptor antagonist restricts healthy and malignant myeloproliferation," Nature Communications, Nature, vol. 14(1), pages 1-28, December.

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