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bioRxiv · 10.1101/2024.03.09.583936

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

Koerber, R.-M.·Krollmann, C.·Cieslak, K.·Tregel, E.·Brümmendorf, T. H.·Koschmieder, S.·Griesshammer, M.·Gütgemann, I.·Brossart, P.·Skoda, R.·Kolbe, C. C.·Latz, E.·Wolf, D.·Teichmann, L. L.
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Abstract

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-1{beta} 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. Key pointsO_LIThe increased IL-1{beta} and IL-18 release in JAK2V617F mutant MPN depends on NLRP3 inflammasome activation C_LIO_LINLRP3 in MPN promotes excess platelet production, granulocytosis, HSPC compartment expansion, splenomegaly and bone marrow fibrosis C_LI

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Koerber, R.-M., Krollmann, C., Cieslak, K., Tregel, E., Brümmendorf, T. H., Koschmieder, S., Griesshammer, M., Gütgemann, I., Brossart, P., Skoda, R., Kolbe, C. C., Latz, E., Wolf, D., Teichmann, L. L.. 2024-03-13. NLRP3-induced systemic inflammation controls the development of JAK2V617F mutant myeloproliferative neoplasms. https://doi.org/10.1101/2024.03.09.583936

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