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

Ruth-Miriam Koerber, Calvin Krollmann, Kevin Cieslak, Elisabeth Tregel, Maria L. Saenz, Tim H. Brümmendorf, Steffen Koschmieder, Martin Griesshammer, Ines Gütgemann, Conny K. Baldauf, Thomas Fischer, Peter Brossart, Carl Christian Kolbe, Eicke Latz, Dominik Wolf () and Lino L. Teichmann ()
Additional contact information
Ruth-Miriam Koerber: University Hospital Bonn, Department of Medicine III
Calvin Krollmann: University Hospital Bonn, Department of Medicine III
Kevin Cieslak: University Hospital Bonn, Department of Medicine III
Elisabeth Tregel: University Hospital Bonn, Department of Medicine III
Maria L. Saenz: University Hospital Bonn, Department of Medicine III
Tim H. Brümmendorf: RWTH Aachen University, Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine
Steffen Koschmieder: RWTH Aachen University, Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine
Martin Griesshammer: University of Bochum, University Clinic for Hematology, Oncology, Haemostaseology and Palliative Care, Johannes Wesling Medical Center Minden
Ines Gütgemann: Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD)
Conny K. Baldauf: Otto-von-Guericke University of Magdeburg, Institute of Molecular and Clinical Immunology
Thomas Fischer: Otto-von-Guericke University of Magdeburg, Institute of Molecular and Clinical Immunology
Peter Brossart: University Hospital Bonn, Department of Medicine III
Carl Christian Kolbe: University Hospitals Bonn, Institute of Innate Immunity
Eicke Latz: University Hospitals Bonn, Institute of Innate Immunity
Dominik Wolf: Medical University of Innsbruck, Internal Medicine V, Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Tyrolean Cancer Research Institute (TKFI), Austrian Comprehensive Cancer Network (ACCN)
Lino L. Teichmann: University Hospital Bonn, Department of Medicine III

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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 investigate whether NLRP3, which precipitates inflammasome assembly upon detection of cellular stress, drives murine JAK2V617F mutant MPN. Deletion of Nlrp3 within the hematopoietic compartment completely prevents increased IL-1β and IL-18 release in MPN. NLRP3 in JAK2V617F hematopoietic cells, but not in JAK2 wild type radioresistant cells, promotes excessive platelet production via stimulation of the direct thrombopoiesis differentiation pathway, as well as granulocytosis. It also promotes expansion of the hematopoietic stem and progenitor cell compartment despite inducing pyroptosis at the same time. Importantly, NLRP3 inflammasome activation enhances bone marrow fibrosis and splenomegaly. Pharmacological blockade of NLRP3 in fully established disease leads to regression of thrombocytosis, splenomegaly and bone marrow fibrosis. These findings suggest that NLRP3 is critical for MPN development and its inhibition represents a new therapeutic intervention for MPN patients.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-65673-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65673-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-65673-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().