Oncogenic KrasG12D causes myeloproliferation via NLRP3 inflammasome activation

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 Shoumariyeh, Christoph Schürch, Geoffroy Andrieux, Nils Venhoff, Annette Schmitt-Graeff, Sandra Duquesne, Dietmar Pfeifer, Matthew A. Cooper, Claudia Lengerke, Melanie Boerries, Justus Duyster, Charlotte M. Niemeyer, Miriam Erlacher, Bruce R. Blazar, Burkard Becher, Olaf Groß, Tilman Brummer and Robert Zeiser ()
Additional contact information
Shaima’a Hamarsheh: Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
Lena Osswald: Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
Benedikt S. Saller: 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
Martina Konantz: University of Basel and University Hospital Basel
Franziska M. Uhl: Medical Center - University of Freiburg, Faculty of Medicine, 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
Justus Duyster: Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
Charlotte M. Niemeyer: German Cancer Research Center (DKFZ)
Miriam Erlacher: German Cancer Research Center (DKFZ)
Bruce R. Blazar: University of Minnesota
Burkard Becher: University of Zurich
Olaf Groß: University Medical Center Freiburg, Faculty of Medicine, University of Freiburg
Tilman Brummer: German Cancer Research Center (DKFZ)
Robert Zeiser: Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15497-1

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