IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms

Lukas F. Mager, Carsten Riether, Christian M. Schürch, Yara Banz, Marie Hélene Wasmer, Regula Stuber, Alexandre P. Theocharides, Xiaohong Li, Yu Xia, Hirohisa Saito, Susumu Nakae, Gabriela M. Baerlocher, Markus G. Manz, Kathy D. McCoy, Andrew J. Macpherson, Adrian F. Ochsenbein, Bruce Beutler, Philippe Krebs

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2579-2591
Number of pages13
JournalJournal of Clinical Investigation
Volume125
Issue number7
DOIs
StatePublished - Jul 1 2015

ASJC Scopus subject areas

  • Medicine(all)

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    Mager, L. F., Riether, C., Schürch, C. M., Banz, Y., Wasmer, M. H., Stuber, R., Theocharides, A. P., Li, X., Xia, Y., Saito, H., Nakae, S., Baerlocher, G. M., Manz, M. G., McCoy, K. D., Macpherson, A. J., Ochsenbein, A. F., Beutler, B., & Krebs, P. (2015). IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms. Journal of Clinical Investigation, 125(7), 2579-2591. https://doi.org/10.1172/JCI77347