title: JAK2(V617I) results in cytokine hypersensitivity without causing an overt myeloproliferative disorder in a mouse transduction-transplantation model.
abstract: A germline JAK2(V617I) point mutation results in hereditary thrombocytosis and shares some phenotypic features with myeloproliferative neoplasm, a hematologic malignancy associated with a somatically acquired JAK2(V617F) mutation. We established a mouse transduction-transplantation model of JAK2(V617I) that recapitulated the phenotype of humans with germline JAK2(V617I). We directly compared the phenotypes of JAK2(V617I) and JAK2(V617F) mice. The JAK2(V617I) mice had increased marrow cellularity with expanded myeloid progenitor and megakaryocyte populations, but this phenotype was less severe than that of JAK2(V617F) mice. JAK2(V617I) resulted in cytokine hyperresponsiveness without constitutive activation in the absence of ligand, whereas JAK2(V617F) resulted in constitutive activation. This may explain why JAK2(V617I) produces a mild myeloproliferative phenotype in the mouse model, as well as in humans with germline JAK2(V617I) mutations.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, Irvine, CA.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Brooks
authors.affiliation: Knight Cancer Institute, Oregon Health & Science University, Portland, OR.
authors.forename: Samuel B
authors.initials: SB
authors.lastname: Luty
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, Irvine, CA.
authors.forename: Hew Yeng
authors.initials: HY
authors.lastname: Lai
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, Irvine, CA.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Morse
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, Irvine, CA.
authors.forename: Thanh Kim
authors.initials: TK
authors.lastname: Nguyen
authors.affiliation: Knight Cancer Institute, Oregon Health & Science University, Portland, OR.
authors.forename: Lacey R
authors.initials: LR
authors.lastname: Royer
authors.affiliation: Knight Cancer Institute, Oregon Health & Science University, Portland, OR.
authors.forename: Anupriya
authors.initials: A
authors.lastname: Agarwal
authors.affiliation: Knight Cancer Institute, Oregon Health & Science University, Portland, OR.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, Irvine, CA. Electronic address: agf@uci.edu.
authors.forename: Angela G
authors.initials: AG
authors.lastname: Fleischman
mesh_terms: D000818:Animals; D016207:Cytokines / Q000502:physiology*; D053614:Janus Kinase 2 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009196:Myeloproliferative Disorders / Q000235:genetics*; D017354:Point Mutation; D033581:Stem Cell Transplantation
chemical_list: D016207:Cytokines; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2