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.
Bibliographical noteFunding Information:
B.R.B. receives remuneration as an advisor to Kamon Pharmaceuticals, Inc., Five Prime Therapeutics Inc., Regeneron Pharmaceuticals, Magenta Therapeutics and BlueRock Therapeutics; research support from Fate Therapeutics, RXi Pharmaceuticals, Alpine Immune Sciences, Inc., Abbvie Inc., BlueRock Therapeutics Leukemia and Lymphoma Society, Childrens’ Cancer Research Fund, KidsFirst Fund and is a co-founder of Tmunity. The other authors have no conflict of interest to disclose.
The authors are thankful to the animal caretakers at University Medical Center Freiburg for their excellent support. We thank Michal Rössler for help with the abstract. This study was supported by the Deutsche Forschungsgemeinschaft, Germany, SFB1160 (R.Z., O.G.), SFB850 (M.B., T.B. and R.Z.), TRR167 (R.Z., O.G.), a Heisenberg professorship (T.B.), DFG individual grant 872/4-1 to R.Z., the Deutsche Krebshilfe (grant number 70113473), the Jose-Carreras Leukemia foundation grant number DJCLS 01 R/2019 (R.Z.), the European Union: ERC Consolidator grant (681012 GvHDCure to R.Z.), an ERC Starting Grant (337689 to O.G.), by the German Federal Ministry of Education and Research (BMBF) within the framework of the e: Med research and funding concept CoNfirm (FKZ 01ZX1708F to M.B.), by the Excellence Strategy of the German Federal and State Governments (CIBSS - EXC 2189 -Project ID 390939984 to R.Z. and O.G.) and EXC 294 BIOSS (R.Z. and T.B.). Two of the authors (CMN, ME) of this publication are members of the European Reference Network for Paediatric Oncology (PEADCAN) - Project ID: 739543, NIH R01 HL56067, R37 AI34495 to B.R.B.
© 2020, The Author(s).
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't