Oncogenic KrasG12D causes myeloproliferation via NLRP3 inflammasome activation View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2020-04-03

AUTHORS

Shaima’a Hamarsheh, Lena Osswald, Benedikt S. Saller, Susanne Unger, Donatella De 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, Robert Zeiser

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. More... »

PAGES

1659

Journal

TITLE

Nature Communications

ISSUE

1

VOLUME

11

Author Affiliations

  • Faculty of Biology, University of Freiburg, Freiburg, Germany
  • Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  • Institute of Neuropathology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  • Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
  • Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
  • Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  • Clinic for Rheumatology and Clinical Immunology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  • University of Freiburg, Freiburg, Germany
  • Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
  • Comprehensive Cancer Centre Freiburg (CCCF), University of Freiburg, Freiburg, Germany
  • Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  • Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, 55455, Minneapolis, MN, USA
  • Centre for Biological Signalling Studies (BIOSS) and Centre for Integrative Biological Signalling Studies (CIBSS), University of Freiburg, Freiburg, Germany
  • Centre for Biological Signalling Studies (BIOSS), University of Freiburg, Freiburg, Germany
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41467-020-15497-1

    DOI

    http://dx.doi.org/10.1038/s41467-020-15497-1

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1126105511

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/32246016


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