Oncogenic KrasG12D causes myeloproliferation via NLRP3 inflammasome activation

Hamarsheh, Shaima'a and Osswald, Lena and Saller, Benedikt S. and Unger, Susanne and De Feo, Donatella and Vinnakota, Janaki Manoja and Konantz, Martina and Uhl, Franziska M. and Becker, Heiko and Lübbert, Michael and Shoumariyeh, Khalid and Schürch, Christoph and Andrieux, Geoffroy and Venhoff, Nils and Schmitt-Graeff, Annette and Duquesne, Sandra and Pfeifer, Dietmar and Cooper, Matthew A. and Lengerke, Claudia and Boerries, Melanie and Duyster, Justus and Niemeyer, Charlotte M. and Erlacher, Miriam and Blazar, Bruce R. and Becher, Burkard and Groß, Olaf and Brummer, Tilman and Zeiser, Robert. (2020) Oncogenic KrasG12D causes myeloproliferation via NLRP3 inflammasome activation. Nature Communications, 11 (1). p. 1659.

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Official URL: https://edoc.unibas.ch/80784/

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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 Kras; G12D; and NLRP3 inflammasome activation in murine and human cells. Mice expressing active Kras; G12D; in the hematopoietic system developed myeloproliferation and cytopenia, which is reversed in Kras; G12D; mice lacking NLRP3 in the hematopoietic system. Therapeutic IL-1-receptor blockade or NLRP3-inhibition reduces myeloproliferation and improves hematopoiesis. Mechanistically, Kras; G12D; -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.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin
UniBasel Contributors:Konantz, Martina
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Nature Publishing Group
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:09 Jun 2021 13:18
Deposited On:09 Jun 2021 13:18

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