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IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Mager Lukas , Riether Carsten, Schürch Christian , Banz Yara , Wasmer Marie-Hélène, Stuber Regula, Theocharides Alexandre, Li Xiaohong , Xia Yu, Hirohisa Saito, Nakae Susumu, Baerlocher Gabriela, Manz Markus , McCoy Kathy , Macpherson Andrew , Ochsenbein Adrian , Beutler Bruce, Krebs Philippe ,
Project Molecular dissection of microbe-induced immunopathlogy
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Original article (peer-reviewed)

Journal The Journal of Clinical Investigation
Title of proceedings The Journal of Clinical Investigation
DOI 10.1172/jci77347

Open Access

Type of Open Access Publisher (Gold Open Access)


Myeloproliferative neoplasms (MPNs) are characterized by the clonal expansion of one or more myeloid cell lineage. In most cases, proliferation of the malignant clone is ascribed to defined genetic alterations. MPNs are also associated with aberrant expression and activity of multiple cytokines; however, the mechanisms by which these cytokines contribute to disease pathogenesis are poorly understood. Here, we reveal a non-redundant role for steady-state IL-33 in supporting dysregulated myelopoiesis in a murine model of MPN. Genetic ablation of the IL-33 signaling pathway was sufficient and necessary to restore normal hematopoiesis and abrogate MPN-like disease in animals lacking the inositol phosphatase SHIP. Stromal cell–derived IL-33 stimulated the secretion of cytokines and growth factors by myeloid and non-hematopoietic cells of the BM, resulting in myeloproliferation in SHIP-deficient animals. Additionally, in the transgenic JAK2V617F model, the onset of MPN was delayed in animals lacking IL-33 in radio-resistant cells. In human BM, we detected increased numbers of IL-33–expressing cells, specifically in biopsies from MPN patients. Exogenous IL-33 promoted cytokine production and colony formation by primary CD34+ MPN stem/progenitor cells from patients. Moreover, IL-33 improved the survival of JAK2V617F-positive cell lines. Together, these data indicate a central role for IL-33 signaling in the pathogenesis of MPNs.