title: Effects of the JAK2 mutation on the hematopoietic stem and progenitor compartment in human myeloproliferative neoplasms.
abstract: The JAK2 V617F mutation is present in the majority of patients with a myeloproliferative neoplasm (MPN) and is sufficient to recapitulate an MPN in murine models. However, the consequences of JAK2 mutations for myeloid differentiation are poorly understood. After systematic analyses of a large cohort of JAK2-mutated MPN patients, we demonstrate in vivo that JAK2 mutations do not alter hematopoietic stem and progenitor cell com-partment size or in vitro behavior but generate expansion of later myeloid differentiation compartments, where homozygous expression of the mutation confers an added proliferative advantage at the single-cell level. In addition, we demonstrate that these findings may be partially explained by the expression pattern of JAK2, which markedly increases on myeloid differentiation. Our findings have potential clinical relevance, as they predict that JAK2 inhibitors may control myeloproliferation, but may have limited efficacy in eradicating the leukemic stem cells that sustain the human MPN.
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK.
authors.forename: Shubha
authors.initials: S
authors.lastname: Anand
authors.forename: Frances
authors.initials: F
authors.lastname: Stedham
authors.forename: Philip
authors.initials: P
authors.lastname: Beer
authors.forename: Emma
authors.initials: E
authors.lastname: Gudgin
authors.forename: Christina A
authors.initials: CA
authors.lastname: Ortmann
authors.forename: Anthony
authors.initials: A
authors.lastname: Bench
authors.forename: Wendy
authors.initials: W
authors.lastname: Erber
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Green
authors.forename: Brian J P
authors.initials: BJ
authors.lastname: Huntly
mesh_terms: D002454:Cell Differentiation / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000473:pathology*; D017354:Point Mutation; D011237:Predictive Value of Tests; D013234:Stem Cells / Q000166:cytology / Q000502:physiology
chemical_list: C507924:JAK2 protein, human; D053614:Janus Kinase 2