TY - JOUR
T1 - IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms
AU - Mager, Lukas F.
AU - Riether, Carsten
AU - Schürch, Christian M.
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
PY - 2015/7/1
Y1 - 2015/7/1
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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U2 - 10.1172/JCI77347
DO - 10.1172/JCI77347
M3 - Article
C2 - 26011644
AN - SCOPUS:84936761972
SN - 0021-9738
VL - 125
SP - 2579
EP - 2591
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 7
ER -