Oncogenic KrasG12D 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-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.

NLRP3 Inflammasome Activation in Cancer: A Double-Edged Sword

“…These phenotypes are often seen in chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML) and more rarely acute myeloid leukemia (AML) patients harboring KRAS mutations. Additionally, we found evidence of NLRP3 inflammasome activation upon analyzing JMML, CMML, and AML patient samples harboring KRAS mutations, providing a stronger evidence of the participation of NLRP3 inflammasome in the disease development ( 49 ). An open question remains how the NLRP3 inflammasome activation drives hematological malignancies, whether by a cell-autonomous signal that promotes cell proliferation directly or via a modification of the TME or both.…”

Immune modulatory effects of oncogenic KRAS in cancer

“…In addition, the pharmacological inhibition of either NLRP3 or IL-1R led to an improvement of the disease phenotypes caused by the KRAS mutation. These findings in mice were reproduced in human chronic myelomonocytic leukaemia (CMML), juvenile myelomonocytic leukaemia (JMML) and acute myeloid leukaemia (AML) harbouring KRAS mutations 55 . Altogether, several lines of evidence have emerged supporting the pro-tumourigenic role of NLRP3 inflammasome in cancer.…”

“…Mechanistically, the groups showed an association of the PD-L1/NLRP3 inflammasome pathway to the recruitment of MDSCs into the tumour tissue causing impairment of the anti-tumour response 54 . Nevertheless, there was no direct link between KRAS mutations and the NLRP3 inflammasome until we recently reported that oncogenic KRAS causes the activation of NLRP3 inflammasome, which has roles in the pathogenesis of KRAS-driven myeloproliferation 55 . Using genetic mouse models as well as patient samples, we observed that the NLRP3 inflammasome had a key role in the development of several features of KRAS-mutant myeloid leukaemia including cytopenia, splenomegaly and myeloproliferation.…”

Inflammatory response in hematopoietic stem and progenitor cells triggered by activating SHP2 mutations evokes blood defects

“…5). A proinflammatory status, with high levels of cytokines, such as IL-1β, TNF-α, GM-CFS, has been previously assigned to JMML in human patients and mouse models, and shown to be generated by myeloid cells (Bagby et al, 1988;Dong et al, 2016;Freedman et al, 1992;Hamarsheh et al, 2020;Zhao et al, 2018). The inflammatory response may be initiated in a cell autonomous way or in response to signals from the microenvironment.…”