title: Deletion of Stat3 in hematopoietic cells enhances thrombocytosis and shortens survival in a JAK2-V617F mouse model of MPN.
abstract: The acquired somatic JAK2-V617F mutation is present in >80% of patients with myeloproliferative neoplasms (MPNs). Stat3 plays a role in hematopoietic homeostasis and might influence the JAK2-V617F-driven MPN phenotype. We crossed our transgenic SclCre;V617F mice with a conditional Stat3 knockout strain and performed bone marrow transplantations into lethally irradiated recipient mice. The deletion of Stat3 increased the platelet numbers in SclCre;V617F;Stat3(fl/fl) mice compared with SclCre;V617F;Stat3(fl/+) or SclCre;V617F;Stat3(+/+) mice. Stat3 deletion also normalized JAK2-V617F-induced neutrophilia. Megakaryocyte progenitors were elevated, especially in the spleen, and a slight increase in myelofibrosis was noted. We observed increased mRNA expression levels of Stat1 and Stat1 target genes and augmented phosphorylation of Stat1 protein in bone marrow and spleen of JAK2-V617F mice after Stat3 deletion. The survival of Stat3-deficient mice expressing JAK2-V617F was reduced. Inflammatory bowel disease, previously associated with shortened survival of Stat3-deficient mice, was less prominent in the bone marrow transplantation setting, possibly by limiting deletion of Stat3 to hematopoietic tissues only. In conclusion, deletion of Stat3 in hematopoietic cells from JAK2-V617F mice did not ameliorate the course of MPN, but rather enhanced thrombocytosis and shortened the overall survival.
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: Takafumi
authors.initials: T
authors.lastname: Shimizu
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: 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: D019943:Amino Acid Substitution; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D019046:Bone Marrow Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality*; D004195:Disease Models, Animal; D018450:Disease Progression; D017353:Gene Deletion; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000378:metabolism / Q000401:mortality*; D010649:Phenylalanine / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D013922:Thrombocytosis / Q000235:genetics*; D014633:Valine / Q000235:genetics
chemical_list: D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D010649:Phenylalanine; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D014633:Valine