title: Deletion of Stat3 enhances myeloid cell expansion and increases the severity of myeloproliferative neoplasms in Jak2V617F knock-in mice.
abstract: The JAK2V617F mutation commonly found in myeloproliferative neoplasms (MPNs) induces constitutive phosphorylation/activation of the signal transducer and activator of transcription 3 (Stat3). However, the contribution of Stat3 in MPN evoked by JAK2V617F remains unknown. To determine the role of Stat3 in JAK2V617F-induced MPN, we generated Stat3-deficient Jak2V617F-expressing mice. Whereas expression of Jak2V617F resulted in a polycythemia vera-like disease characterized by increased red blood cells (RBCs), hematocrit, neutrophils and platelets in the peripheral blood of Jak2V617F knock-in mice, deletion of Stat3 slightly reduced RBC and hematocrit parameters and modestly increased platelet numbers in Jak2V617F knock-in mice. Moreover, deletion of Stat3 significantly increased the neutrophil counts/percentages and markedly reduced the survival of mice expressing Jak2V617F. These phenotypic manifestations were reproduced upon bone marrow (BM) transplantation into wild-type animals. Flow cytometric analysis showed increased hematopoietic stem cell and granulocyte-macrophage progenitor populations in the BM and spleens of Stat3-deficient Jak2V617F mice. Stat3 deficiency also caused a marked expansion of Gr-1+/Mac-1+ myeloid cells in Jak2V617F knock-in mice. Histopathologic analysis revealed marked increase in granulocytes in the BM, spleens and livers of Stat3-deficient Jak2V617F-expressing mice. Together, these results suggest that deletion of Stat3 increases the severity of MPN induced by Jak2V617F.
authors.affiliation: Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, USA.
authors.forename: D
authors.initials: D
authors.lastname: Yan
authors.affiliation: Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, USA.
authors.forename: F
authors.initials: F
authors.lastname: Jobe
authors.affiliation: Department of Pathology, SUNY Upstate Medical University, Syracuse, NY, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Hutchison
authors.affiliation: Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, USA.
authors.forename: G
authors.initials: G
authors.lastname: Mohi
mesh_terms: D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D055014:Granulocyte-Macrophage Progenitor Cells / Q000378:metabolism / Q000473:pathology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D053614:Janus Kinase 2 / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology*; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000502:physiology*; D012720:Severity of Illness Index; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2