Role of the NLRP3 Inflammasome in Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal diseases characterized by a hypercellular bone marrow, splenomegaly and myelofibrosis. Driver mutations in the JAK2, MPL and CALR gene have facilitated the molecular diagnosis, but causal treatment options are still missing. Clinically, some of the symptoms can be related to the known chronic inflammation in MPN.  Established JAK inhibitors reduce symptoms linked to inflammation, though molecular responses and complete remissions in MPN patients are not observed. Recent investigations implicate activation of the NLRP3 inflammasome in other hematologic malignancies, such as myelodysplastic syndromes. Here, we seek to investigate the role of NLRP3 in MPN in a human cohort and in the murine VavCre/JAK2V617F/+ knock-in MPN model. Others and we could demonstrate that pro-inflammatory cytokine production is broadly upregulated in MPN. In particular, the concentration of inflammasome-dependent cytokines is substantially increased in sera from MPN patients and MPN mice. In line with that, gene expression analysis of human MPN samples revealed higher transcript levels of inflammasome-associated genes than those from healthy controls. Using bone marrow chimera and our murine NLRP3+/+VavCre/JAK2V617F/+ and NLRP3-/-VavCre/JAK2V617F/+ knock-in MPN model we will define the cellular compartment in which inflammasome activation contributes to MPN development. In addition, we will conduct a drug trial with a novel NLRP3-inhibitor in the murine MPN model to directly test the effects of disrupting inflammation by pharmaceutical blockade. The goal of this project is to establish the role of NLRP3 in MPN and to evaluate it as a new therapeutic target.