| First Author | Hamarsheh S | Year | 2020 |
| Journal | Nat Commun | Volume | 11 |
| Issue | 1 | Pages | 1659 |
| PubMed ID | 32246016 | Mgi Jnum | J:287098 |
| Mgi Id | MGI:6406145 | Doi | 10.1038/s41467-020-15497-1 |
| Citation | Hamarsheh S, et al. (2020) Oncogenic Kras(G12D) causes myeloproliferation via NLRP3 inflammasome activation. Nat Commun 11(1):1659 |
| abstractText | 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-1beta 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-1beta axis. This paves the way for a therapeutic approach based on immune modulation via NLRP3 blockade in KRAS-mutant myeloid malignancies. |
