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

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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

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Neoplasms
Cytokines
Stem Cells
Myelopoiesis
Animal Diseases
Interleukin-33
Hematopoiesis
Cell Lineage
Myeloid Cells
Stromal Cells
Radio
Intercellular Signaling Peptides and Proteins
Clone Cells
Biopsy
Cell Line
Survival

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Mager, L. F., Riether, C., Schürch, C. M., Banz, Y., Wasmer, M. H., Stuber, R., ... 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

IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms. / Mager, Lukas F.; Riether, Carsten; Schürch, Christian M.; Banz, Yara; Wasmer, Marie Hélene; Stuber, Regula; Theocharides, Alexandre P.; Li, Xiaohong; Xia, Yu; Saito, Hirohisa; Nakae, Susumu; Baerlocher, Gabriela M.; Manz, Markus G.; McCoy, Kathy D.; Macpherson, Andrew J.; Ochsenbein, Adrian F.; Beutler, Bruce; Krebs, Philippe.

In: Journal of Clinical Investigation, Vol. 125, No. 7, 01.07.2015, p. 2579-2591.

Research output: Contribution to journalArticle

Mager, LF, Riether, C, Schürch, CM, Banz, Y, Wasmer, MH, Stuber, R, Theocharides, AP, Li, X, Xia, Y, Saito, H, Nakae, S, Baerlocher, GM, Manz, MG, McCoy, KD, Macpherson, AJ, Ochsenbein, AF, Beutler, B & Krebs, P 2015, 'IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms', Journal of Clinical Investigation, vol. 125, no. 7, pp. 2579-2591. https://doi.org/10.1172/JCI77347
Mager LF, Riether C, Schürch CM, Banz Y, Wasmer MH, Stuber R et al. IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms. Journal of Clinical Investigation. 2015 Jul 1;125(7):2579-2591. https://doi.org/10.1172/JCI77347
Mager, Lukas F. ; Riether, Carsten ; Schürch, Christian M. ; Banz, Yara ; Wasmer, Marie Hélene ; Stuber, Regula ; Theocharides, Alexandre P. ; Li, Xiaohong ; Xia, Yu ; Saito, Hirohisa ; Nakae, Susumu ; Baerlocher, Gabriela M. ; Manz, Markus G. ; McCoy, Kathy D. ; Macpherson, Andrew J. ; Ochsenbein, Adrian F. ; Beutler, Bruce ; Krebs, Philippe. / IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms. In: Journal of Clinical Investigation. 2015 ; Vol. 125, No. 7. pp. 2579-2591.
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AU - Riether, Carsten

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AU - Banz, Yara

AU - Wasmer, Marie Hélene

AU - Stuber, Regula

AU - Theocharides, Alexandre P.

AU - Li, Xiaohong

AU - Xia, Yu

AU - Saito, Hirohisa

AU - Nakae, Susumu

AU - Baerlocher, Gabriela M.

AU - Manz, Markus G.

AU - McCoy, Kathy D.

AU - Macpherson, Andrew J.

AU - Ochsenbein, Adrian F.

AU - Beutler, Bruce

AU - Krebs, Philippe

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N2 - 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.

AB - 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.

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