Oncogenic KrasG12D causes myeloproliferation via NLRP3 inflammasome activation
| Autor: | Franziska M. Uhl, Dietmar Pfeifer, Melanie Boerries, Donatella De Feo, Shaima’a Hamarsheh, Heiko Becker, Benedikt S. Saller, Lena Osswald, Claudia Lengerke, Janaki Manoja Vinnakota, Miriam Erlacher, Geoffroy Andrieux, Justus Duyster, Sandra Duquesne, Robert Zeiser, Martina Konantz, Mark E. Cooper, Annette Schmitt-Graeff, Tilman Brummer, Christoph Schürch, Charlotte M. Niemeyer, Nils Venhoff, Olaf Groß, Michael Lübbert, Khalid Shoumariyeh, Burkhard Becher, Susanne Unger, Bruce R. Blazar |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Myeloid Science General Physics and Astronomy medicine.disease_cause General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine hemic and lymphatic diseases Myeloproliferation medicine lcsh:Science Multidisciplinary integumentary system Chemistry Myeloid leukemia Inflammasome General Chemistry medicine.disease 3. Good health Leukemia Haematopoiesis 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer research lcsh:Q KRAS Signal transduction medicine.drug |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-17 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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