Journal Article

Oncogenic KrasG12D causes myeloproliferation via NLRP3 inflammasome activation

Boerries, Melanie, Osswald, Lena, Konantz, Martina, Duyster, Justus, Saller, Benedikt S., Venhoff, Nils, Erlacher, Miriam, Zeiser, Robert, Unger, Susanne, Shoumariyeh, Khalid, Duquesne, Sandra, Schmitt-Graeff, Annette, Pfeifer, Dietmar, De Feo, Donatella, Becher, Burkard, Uhl, Franziska M., Vinnakota, Janaki Manoja, Niemeyer, Charlotte M., Blazar, Bruce R., Andrieux, Geoffroy, Lengerke, Claudia, Brummer, Tilman, Lübbert, Michael, Groß, Olaf, Schürch, Christoph, Hamarsheh, Shaima’a, Cooper, Matthew A., Becker, Heiko

2020

Overview

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. Oncogenic Ras mutations are common drivers in myeloid leukemia. Here, the authors show in patient cells and in mice that oncogenic K-Ras activates NLRP3 inflammasome to drive myeloproliferation, which can be reversed by genetic or pharmacologic NLRP3 blockade.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/31 / 13/51 / 14/63 / 631/250/1904 / 631/250/262/2106/2517 / 631/67/1059/602 / 64/60 / 692/4028/67/1990/2331 / Activation / Cytopenia / Hematopoiesis / Hematopoietic system / Humanities and Social Sciences / IL-1β / Immunomodulation / Inflammasomes / Inflammation / Interleukin 1 / K-Ras protein / Leukemia / multidisciplinary / Mutants / Mutation / Myeloid leukemia / Myeloproliferation / Rac1 protein / Reactive oxygen species / Science / Science (multidisciplinary)