title: Expression of TEL-JAK2 in primary human hematopoietic cells drives erythropoietin-independent erythropoiesis and induces myelofibrosis in vivo.
abstract: Activation of JAK2 by chromosomal translocation or point mutation is a recurrent event in hematopoietic malignancies, including acute leukemias and myeloproliferative disorders. Although the effects of activated JAK2 signaling have been examined in cell lines and murine models, the functional consequences of deregulated JAK2 in the context of human hematopoietic cells are currently unknown. Here we report that expression of TEL-JAK2, a constitutively active variant of the JAK2 kinase, in lineage-depleted human umbilical cord blood cells results in erythropoietin-independent erythroid differentiation in vitro and induces the rapid development of myelofibrosis in an in vivo NOD/SCID xenotransplantation assay. These studies provide functional evidence that activated JAK2 signaling in primitive human hematopoietic cells is sufficient to drive key processes implicated in the pathophysiology of polycythemia vera and idiopathic myelofibrosis. Furthermore, they describe an in vivo model of myelofibrosis initiated with primary cells, highlighting the utility of the NOD/SCID xenotransplant system for the development of experimental models of human hematopoietic malignancies.
authors.affiliation: Division of Cell and Molecular Biology and Department of Pathology, University Health Network, Toronto, Ontario, Canada M5G 1L7.
authors.forename: J A
authors.initials: JA
authors.lastname: Kennedy
authors.forename: F
authors.initials: F
authors.lastname: Barabé
authors.forename: B J
authors.initials: BJ
authors.lastname: Patterson
authors.forename: J
authors.initials: J
authors.lastname: Bayani
authors.forename: J A
authors.initials: JA
authors.lastname: Squire
authors.forename: D L
authors.initials: DL
authors.lastname: Barber
authors.forename: J E
authors.initials: JE
authors.lastname: Dick
mesh_terms: D000818:Animals; D004920:Erythropoiesis / Q000502:physiology*; D004921:Erythropoietin / Q000378:metabolism; D015870:Gene Expression; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D055728:Primary Myelofibrosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous; D053614:Janus Kinase 2; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D004921:Erythropoietin; D015514:Oncogene Proteins, Fusion; D011994:Recombinant Proteins; C108603:TEL-JAK2 fusion protein, human; D053614:Janus Kinase 2; D000097764:ETS Translocation Variant 6 Protein