title: JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F-positive essential thrombocythemia.
abstract: The JAK2 V617F mutation is found in most patients with a myeloproliferative neoplasm and is sufficient to produce a myeloproliferative phenotype in murine retroviral transplantation or transgenic models. However, several lines of evidence suggest that disease phenotype is influenced by the level of mutant JAK2 signaling, and we have therefore generated a conditional knock-in mouse in which a human JAK2 V617F is expressed under the control of the mouse Jak2 locus. Human and murine Jak2 transcripts are expressed at similar levels, and mice develop modest increases in hemoglobin and platelet levels reminiscent of human JAK2 V617F-positive essential thrombocythemia. The phenotype is transplantable and accompanied by increased terminal erythroid and megakaryocyte differentiation together with increased numbers of clonogenic progenitors, including erythropoietin-independent erythroid colonies. Unexpectedly, JAK2(V617F) mice develop reduced numbers of lineage(-)Sca-1(+)c-Kit(+) cells, which exhibit increased DNA damage, reduced apoptosis, and reduced cell cycling. Moreover, competitive bone marrow transplantation studies demonstrated impaired hematopoietic stem cell function in JAK2(V617F) mice. These results suggest that the chronicity of human myeloproliferative neoplasms may reflect a balance between impaired hematopoietic stem cell function and the accumulation of additional mutations.
authors.affiliation: Cambridge Institute for Medical Research, Department of Haematology, University of Cambridge, United Kingdom.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Dominik
authors.initials: D
authors.lastname: Spensberger
authors.forename: Jong Sook
authors.initials: JS
authors.lastname: Ahn
authors.forename: Shubha
authors.initials: S
authors.lastname: Anand
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beer
authors.forename: Cedric
authors.initials: C
authors.lastname: Ghevaert
authors.forename: Edwin
authors.initials: E
authors.lastname: Chen
authors.forename: Ariel
authors.initials: A
authors.lastname: Forrai
authors.forename: Linda M
authors.initials: LM
authors.lastname: Scott
authors.forename: Rita
authors.initials: R
authors.lastname: Ferreira
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.forename: Steve P
authors.initials: SP
authors.lastname: Watson
authors.forename: Pentao
authors.initials: P
authors.lastname: Liu
authors.forename: Wendy N
authors.initials: WN
authors.lastname: Erber
authors.forename: Brian J P
authors.initials: BJ
authors.lastname: Huntly
authors.forename: Katrin
authors.initials: K
authors.lastname: Ottersbach
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Green
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D002453:Cell Cycle; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D055879:Gene Knock-In Techniques; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D019426:Integrases / Q000378:metabolism; D053614:Janus Kinase 2 / Q000502:physiology*; D051379:Mice; D017354:Point Mutation / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013920:Thrombocythemia, Essential / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*
chemical_list: D012333:RNA, Messenger; D053614:Janus Kinase 2; C045073:Cre recombinase; D019426:Integrases