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Oncogenic KrasG12D causes myeloproliferation via NLRP3 inflammasome activation

Author

Listed:
  • Shaima’a Hamarsheh

    (Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
    University of Freiburg)

  • Lena Osswald

    (Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg)

  • Benedikt S. Saller

    (University of Freiburg
    University Medical Center Freiburg, Faculty of Medicine, University of Freiburg)

  • Susanne Unger

    (University of Zurich)

  • Donatella Feo

    (University of Zurich)

  • Janaki Manoja Vinnakota

    (Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
    University of Freiburg)

  • Martina Konantz

    (University of Basel and University Hospital Basel)

  • Franziska M. Uhl

    (Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
    University of Freiburg)

  • Heiko Becker

    (Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg)

  • Michael Lübbert

    (Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg)

  • Khalid Shoumariyeh

    (Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg)

  • Christoph Schürch

    (University of Basel and University Hospital Basel)

  • Geoffroy Andrieux

    (University of Freiburg)

  • Nils Venhoff

    (University Medical Center Freiburg, Faculty of Medicine, University of Freiburg)

  • Annette Schmitt-Graeff

    (University of Freiburg)

  • Sandra Duquesne

    (Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg)

  • Dietmar Pfeifer

    (Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg)

  • Matthew A. Cooper

    (University of Queensland)

  • Claudia Lengerke

    (University of Basel and University Hospital Basel)

  • Melanie Boerries

    (University of Freiburg
    German Cancer Research Center (DKFZ)
    University of Freiburg)

  • Justus Duyster

    (Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
    German Cancer Research Center (DKFZ)
    University of Freiburg)

  • Charlotte M. Niemeyer

    (German Cancer Research Center (DKFZ)
    University of Freiburg
    University Medical Center Freiburg, Faculty of Medicine, University of Freiburg)

  • Miriam Erlacher

    (German Cancer Research Center (DKFZ)
    University of Freiburg
    University Medical Center Freiburg, Faculty of Medicine, University of Freiburg)

  • Bruce R. Blazar

    (University of Minnesota)

  • Burkard Becher

    (University of Zurich)

  • Olaf Groß

    (University Medical Center Freiburg, Faculty of Medicine, University of Freiburg
    University of Freiburg)

  • Tilman Brummer

    (German Cancer Research Center (DKFZ)
    University of Freiburg
    University of Freiburg
    University of Freiburg)

  • Robert Zeiser

    (Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
    German Cancer Research Center (DKFZ)
    University of Freiburg
    University of Freiburg)

Abstract

Oncogenic Ras mutations occur in various leukemias. It was unclear if, besides the direct transforming effect via constant RAS/MEK/ERK signaling, an inflammation-related effect of KRAS contributes to the disease. Here, we identify a functional link between oncogenic KrasG12D and NLRP3 inflammasome activation in murine and human cells. Mice expressing active KrasG12D in the hematopoietic system developed myeloproliferation and cytopenia, which is reversed in KrasG12D mice lacking NLRP3 in the hematopoietic system. Therapeutic IL-1-receptor blockade or NLRP3-inhibition reduces myeloproliferation and improves hematopoiesis. Mechanistically, KrasG12D-RAC1 activation induces reactive oxygen species (ROS) production causing NLRP3 inflammasome-activation. In agreement with our observations in mice, patient-derived myeloid leukemia cells exhibit KRAS/RAC1/ROS/NLRP3/IL-1β axis activity. Our findings indicate that oncogenic KRAS not only act via its canonical oncogenic driver function, but also enhances the activation of the pro-inflammatory RAC1/ROS/NLRP3/IL-1β axis. This paves the way for a therapeutic approach based on immune modulation via NLRP3 blockade in KRAS-mutant myeloid malignancies.

Suggested Citation

  • Shaima’a Hamarsheh & Lena Osswald & Benedikt S. Saller & Susanne Unger & Donatella Feo & Janaki Manoja Vinnakota & Martina Konantz & Franziska M. Uhl & Heiko Becker & Michael Lübbert & Khalid Shoumari, 2020. "Oncogenic KrasG12D causes myeloproliferation via NLRP3 inflammasome activation," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15497-1
    DOI: 10.1038/s41467-020-15497-1
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