Oncogenic Kras^G12D causes myeloproliferation via NLRP3 inflammasome activation.

ABSTRACT: 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-activatio

SUBMITTER: Hamarsheh S 

PROVIDER: S-EPMC7125138 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature