NLRP3-induced systemic inflammation controls the development of JAK2V617F mutant myeloproliferative neoplasms

The development of Philadelphia chromosome-negative classical myeloproliferative neoplasms (MPN) involves an inflammatory process that facilitates outgrowth of the malignant clone and correlates with clinical outcome measures. This raises the question to which extent inflammatory circuits in MPN depend on activation of innate immune sensors. Here, we investigated whether NLRP3, which precipitates inflammasome assembly upon detection of cellular stress, drives murine JAK2V617F mutant MPN. Deletion of Nlrp3 within the hematopoietic compartment completely prevented increased IL-1β and IL-18 release in MPN. NLRP3 in JAK2V617F hematopoietic cells, but not in JAK2 wild type radioresistant cells, promoted excessive platelet production via stimulation of the direct thrombopoiesis differentiation pathway, as well as granulocytosis. It also promoted expansion of the hematopoietic stem and progenitor cell compartment despite inducing pyroptosis at the same time. Importantly, NLRP3 inflammasome activation enhanced bone marrow fibrosis and splenomegaly. Pharmacological blockade of NLRP3 in fully established disease led to regression of thrombocytosis and splenomegaly. These findings suggest that NLRP3 is critical for MPN development and its inhibition represents a new therapeutic intervention for MPN patients. ### Competing Interest Statement RMK received honoraria from Stemline. THB served as a consultant or invited speaker for Astra-Zeneca, Gilead, Janssen, Merck, Novartis and Pfizer and received research funding from Novartis and Pfizer. SK reports research grant/funding from Geron, Janssen, AOP Pharma, and Novartis; consulting fees from Pfizer, Incyte, Ariad, Novartis, AOP Pharma, Bristol Myers Squibb, Celgene, Geron, Janssen, CTI BioPharma, Roche, Bayer, GSK, Sierra Oncology, and PharmaEssentia; payment or honoraria from Novartis, BMS/Celgene, Pfizer; travel/accommodation support from Alexion, Novartis, Bristol Myers Squibb, Incyte, AOP Pharma, CTI BioPharma, Pfizer, Celgene, Janssen, Geron, Roche, AbbVie, GSK, Sierra Oncology, and Karthos; a patent issued for a BET inhibitor at RWTH Aachen University; advisory board activity for from Pfizer, Incyte, Ariad, Novartis, AOP Pharma, BMS, Celgene, Geron, Janssen, CTI BioPharma, Roche, Bayer, GSK, Sierra Oncology, and PharmaEssentia. MG reports speaker bureau and consultancy for AOP Orphan, Celgene, CTI, Novartis, and Shire. IG received funding from aTyr. RCS is a scientific advisor/SAB member and has equity in Ajax Therapeutics, he consulted for and/or received honoraria from Novartis, BMS/Celgene, AOP, GSK, Baxalta and Pfizer. CCK is an employee of Bayer. EL is co-founder and consultant to IFM Therapeutics, Odyssey Therapeutics and a Stealth Biotech company. DW served as a consultant or invited speaker for Novartis, Roche, BMS, Gilead, Janssen, MSD, AOP Orphan and Pfizer and received research funding from Novartis, BMS, AOP Orphan and Pfizer. LLT reports honoraria from AOP Orphan, Boehringer Ingelheim, BMS and Novartis; consultancy for Astellas, Blueprint, BMS, GSK, Jazz Pharmaceuticals, Pfizer, and Sobi. The remaining authors declare no competing financial interests.