title: 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.forename: Lukas F
authors.initials: LF
authors.lastname: Mager
authors.forename: Carsten
authors.initials: C
authors.lastname: Riether
authors.forename: Christian M
authors.initials: CM
authors.lastname: Schürch
authors.forename: Yara
authors.initials: Y
authors.lastname: Banz
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Wasmer
authors.forename: Regula
authors.initials: R
authors.lastname: Stuber
authors.forename: Alexandre P
authors.initials: AP
authors.lastname: Theocharides
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Xia
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Saito
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakae
authors.forename: Gabriela M
authors.initials: GM
authors.lastname: Baerlocher
authors.forename: Markus G
authors.initials: MG
authors.lastname: Manz
authors.forename: Kathy D
authors.initials: KD
authors.lastname: McCoy
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Macpherson
authors.forename: Adrian F
authors.initials: AF
authors.lastname: Ochsenbein
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
authors.forename: Philippe
authors.initials: P
authors.lastname: Krebs
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D038042:Myelopoiesis / Q000235:genetics / Q000502:physiology; D009196:Myeloproliferative Disorders / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D034521:Nuclear Matrix-Associated Proteins; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C506536:IL33 protein, human; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D047908:Intracellular Signaling Peptides and Proteins; D050505:Mutant Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D034521:Nuclear Matrix-Associated Proteins; D018123:Receptors, Interleukin; C450144:Styx protein, mouse; D051193:Toll-Like Receptors; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases