title: Loss of Stat1 decreases megakaryopoiesis and favors erythropoiesis in a JAK2-V617F-driven mouse model of MPNs.
abstract: The interferon-γ (IFNγ)/signal transducer and activator of transcription 1 (Stat1) pathway shows higher activity in patients with essential thrombocythemia (ET) than in polycythemia vera (PV) and was proposed to be promoting the ET phenotype. We explored the phenotypic consequences of Stat1 deficiency on the effects of Janus kinase 2 (JAK2)-V617F in vivo by crossing mice expressing JAK2-V617F with Stat1 knockout mice. JAK2-V617F;Stat1(-/-) double transgenic mice showed higher red cell parameters and lower platelet counts compared with JAK2-V617F;Stat1(+/+) mice. Bone marrow transplantation reproduced these phenotypic changes in wild-type recipients, demonstrating that the effect of Stat1 is cell-intrinsic and does not require a Stat1-deficient microenvironment. Deletion of Stat1 increased burst-forming unit-erythroid and reduced colony-forming unit-megakaryocyte colony formation driven by JAK2-V617F, but was not sufficient to completely normalize the platelet count. Gata1, a key regulator of megakaryopoiesis and erythropoiesis, was decreased in Stat1-deficient platelets. V617F transgenic mice with thrombocytosis had higher serum levels of IFNγ than normal controls and patients with ET showed higher IFNγ serum levels than patients with PV. Together, these results support the concept that activating Stat1 in the presence of JAK2-V617F, for example, through IFNγ, constrains erythroid differentiation and promotes megakaryocytic development, resulting in ET phenotype.
authors.affiliation: Department of Biomedicine, Experimental Hematology and.
authors.forename: Adrian
authors.initials: A
authors.lastname: Duek
authors.affiliation: Department of Biomedicine, Experimental Hematology and.
authors.forename: Pontus
authors.initials: P
authors.lastname: Lundberg
authors.affiliation: Department of Biomedicine, Experimental Hematology and.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Biomedicine, Experimental Hematology and.
authors.forename: Jean
authors.initials: J
authors.lastname: Grisouard
authors.affiliation: Department of Biomedicine, Experimental Hematology and.
authors.forename: Axel
authors.initials: A
authors.lastname: Karow
authors.affiliation: Department of Biomedicine, Experimental Hematology and.
authors.forename: Lucia
authors.initials: L
authors.lastname: Kubovcakova
authors.affiliation: Department of Biomedicine, Experimental Hematology and.
authors.forename: Hui
authors.initials: H
authors.lastname: Hao-Shen
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Dirnhofer
authors.affiliation: Department of Biomedicine, Experimental Hematology and.
authors.forename: Radek C
authors.initials: RC
authors.lastname: Skoda
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019046:Bone Marrow Neoplasms / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000379:methods; D004195:Disease Models, Animal; D004920:Erythropoiesis / Q000235:genetics*; D005260:Female; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D011087:Polycythemia Vera / Q000097:blood / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D013920:Thrombocythemia, Essential / Q000097:blood / Q000235:genetics / Q000378:metabolism; D034061:Thrombopoiesis / Q000235:genetics*
chemical_list: D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D007371:Interferon-gamma; D053614:Janus Kinase 2