title: JAK2V617F-mutant megakaryocytes contribute to hematopoietic stem/progenitor cell expansion in a model of murine myeloproliferation.
abstract: The myeloproliferative neoplasms (MPNs) are characterized by hematopoietic stem/progenitor cell (HSPC) expansion and overproduction of mature blood cells. The JAK2V617Fmutation is present in hematopoietic cells in a majority of patients with MPNs, but the mechanism(s) responsible for MPN stem cell expansion remain incomplete. One hallmark feature of the marrow in patients with MPNs is megakaryocyte (MK) hyperplasia. We report here that mice bearing a human JAK2V617Fgene restricted exclusively to the MK lineage develop many of the features of a MPN. Specifically, these mice exhibit thrombocytosis, splenomegaly, increased numbers of marrow and splenic hematopoietic progenitors and a substantial expansion of HSPCs. In addition, wild-type mice transplanted with cells from JAK2V617F-bearing MK marrow develop a myeloproliferative syndrome with thrombocytosis and erythrocytosis as well as pan-hematopoietic progenitor and stem cell expansion. As marrow histology in this murine model of myeloproliferation reveals a preferentially perivascular localization of JAK2V617F-mutant MKs and an increased marrow sinusoid vascular density, it adds to accumulating data that MKs are an important component of the marrow HSPC niche, and that MK expansion might indirectly contribute to the critical role of the thrombopoietin/c-Mpl signaling pathway in HSPC maintenance and expansion.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Northport VA Medical Center, Northport, NY, USA.|Department of Medicine, Division of Hematology-Oncology, Stony Brook University, Stony Brook, NY, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhan
authors.affiliation: Department of Pathology, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Stony Brook University, Stony Brook, NY, USA.
authors.forename: C H S
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Office of the Sr Vice President, Health Sciences, Stony Brook Medicine, NY, USA.
authors.forename: K
authors.initials: K
authors.lastname: Kaushansky
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D008533:Megakaryocytes / Q000378:metabolism*; D051379:Mice; D020125:Mutation, Missense; D009196:Myeloproliferative Disorders / Q000473:pathology; D055153:Stem Cell Niche
chemical_list: C507924:JAK2 protein, human; D053614:Janus Kinase 2