title: JAK2V617F expression in mice amplifies early hematopoietic cells and gives them a competitive advantage that is hampered by IFNα.
abstract: The acquired gain-of-function V617F mutation in the Janus Kinase 2 (JAK2(V617F)) is the main mutation involved in BCR/ABL-negative myeloproliferative neoplasms (MPNs), but its effect on hematopoietic stem cells as a driver of disease emergence has been questioned. Therefore, we reinvestigated the role of endogenous expression of JAK2(V617F) on early steps of hematopoiesis as well as the effect of interferon-α (IFNα), which may target the JAK2(V617F) clone in humans by using knock-in mice with conditional expression of JAK2(V617F) in hematopoietic cells. These mice develop a MPN mimicking polycythemia vera with large amplification of myeloid mature and precursor cells, displaying erythroid endogenous growth and progressing to myelofibrosis. Interestingly, early hematopoietic compartments [Lin-, LSK, and SLAM (LSK/CD48-/CD150+)] increased with the age. Competitive repopulation assays demonstrated disease appearance and progressive overgrowth of myeloid, Lin-, LSK, and SLAM cells, but not lymphocytes, from a low number of engrafted JAK2(V617F) SLAM cells. Finally, IFNα treatment prevented disease development by specifically inhibiting JAK2(V617F) cells at an early stage of differentiation and eradicating disease-initiating cells. This study shows that JAK2(V617F) in mice amplifies not only late but also early hematopoietic cells, giving them a proliferative advantage through high cell cycling and low apoptosis that may sustain MPN emergence but is lost upon IFNα treatment.
authors.affiliation: INSERM U.1009, Institut Gustave Roussy,Villejuif, France.
authors.forename: Salma
authors.initials: S
authors.lastname: Hasan
authors.forename: Catherine
authors.initials: C
authors.lastname: Lacout
authors.forename: Caroline
authors.initials: C
authors.lastname: Marty
authors.forename: Marie
authors.initials: M
authors.lastname: Cuingnet
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Villeval
mesh_terms: D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation; D002453:Cell Cycle; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics; D010641:Phenotype; D011087:Polycythemia Vera / Q000235:genetics; D055728:Primary Myelofibrosis / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology
chemical_list: D016898:Interferon-alpha; D053614:Janus Kinase 2