title: Distinct roles for long-term hematopoietic stem cells and erythroid precursor cells in a murine model of Jak2V617F-mediated polycythemia vera.
abstract: In the current model of the pathogenesis of polycythemia vera (PV), the JAK2V617F mutation arises in hematopoietic stem cells (HSCs) that maintain the disease, while erythroid precursor populations expand, resulting in excessive red blood cell production. We examined the role of these specific cell populations using a conditional Jak2V617F knockin murine model. We demonstrate that the most immature long-term (LT) HSCs are solely responsible for initiating and maintaining the disease in vivo and that Jak2V617F mutant LT-HSCs dominate hematopoiesis over time. When we induced Jak2V617F expression in erythropoietin receptor expressing precursor cells, the mice developed elevated hematocrit, expanded erythroid precursors, and suppressed erythropoietin levels. However, the disease phenotype was significantly attenuated compared with mice expressing Jak2V617F in LT-HSCs. In addition to developing a PV phenotype, all mice transplanted with Jak2V617F LT-HSCs underwent myelofibrotic transformation over time. These findings recapitulate the development of post-PV myelofibrosis in human myeloproliferative neoplasms. In aggregate, these results demonstrate the distinct roles of LT-HSCs and erythroid precursors in the pathogenesis of PV.
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Mullally
authors.forename: Luke
authors.initials: L
authors.lastname: Poveromo
authors.forename: Rebekka K
authors.initials: RK
authors.lastname: Schneider
authors.forename: Fatima
authors.initials: F
authors.lastname: Al-Shahrour
authors.forename: Steven W
authors.initials: SW
authors.lastname: Lane
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D019070:Cell Lineage / Q000502:physiology; D002999:Clone Cells / Q000166:cytology; D004195:Disease Models, Animal; D041905:Erythroid Cells / Q000166:cytology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology*; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D010641:Phenotype; D017354:Point Mutation / Q000502:physiology; D011087:Polycythemia Vera / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D055728:Primary Myelofibrosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology
chemical_list: C507926:Jak2 protein, mouse; D053614:Janus Kinase 2