Abstract
AbstractOncogenic 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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference41 articles.
1. Ahmad, E. I., Gawish, H. H., Al Azizi, N. M. & Elhefni, A. M. The prognostic impact of K-RAS mutations in adult acute myeloid leukemia patients treated with high-dose cytarabine. Onco Targets Ther. 4, 115–121 (2011).
2. Neubauer, A. et al. Prognostic importance of mutations in the ras proto-oncogenes in de novo acute myeloid leukemia. Blood 83, 1603–1611 (1994).
3. Itzykson, R. et al. Malcovati L. diagnosis and treatment of chronic myelomonocytic leukemias in adults: recommendations from the European Hematology Association and the European LeukemiaNet. Hemasphere 29, e150 (2018).
4. Merlevede, J. et al. Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents. Nat. Commun. 24, 10767 (2016).
5. Sheng, X. M. et al. Mutations of the RAS genes in childhood acute myeloid leukemia, myelodysplastic syndrome and juvenile chronic myelocytic leukemia. Leuk. Res. 21, 697–701 (1997).
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