IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms
Lukas F. Mager, Carsten Riether, Christian M. Schürch, Yara Banz, Marie-Hélène 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
Lukas F. Mager, Carsten Riether, Christian M. Schürch, Yara Banz, Marie-Hélène 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
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Research Article Hematology

IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms

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.

Authors

Lukas F. Mager, Carsten Riether, Christian M. Schürch, Yara Banz, Marie-Hélène 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

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Figure 9

Models for the development of MPN in the BM microenvironment.

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Models for the development of MPN in the BM microenvironment. (A) Model ...
(A) Model for SHIP-deficient mice. Stromal cell–derived IL-33 is released under stress or steady-state conditions through a pathway that is yet to be determined. IL-33 engages its receptor ST2 on stromal cells or, preferentially, on a committed population of myeloid cells. Signal transduction via the ST2→MyD88→IRAK4 axis promotes the secretion of several cytokines and growth factors promoting myoproliferation — among others GM-CSF and IL-6 — that bind to their respective receptors and activate the JAK2/STAT5 pathway (49). SHIP is a negative regulator in this process, and impaired SHIP-mediated inhibition results in MPN-like disease. (B) IL-33 released by stromal cells in the human BM engages ST2 receptor on CD34+ HSPCs. Activation of cell signaling downstream of ST2 leads to the production of autocrine cytokines and growth factors that support proliferation.