title: Dysregulated hematopoiesis and a progressive neurological disorder induced by expression of an activated form of the human common beta chain in transgenic mice.
abstract: Previously we described activating mutations of hbetac, the common signaling subunit of the receptors for the hematopoietic and inflammatory cytokines, GM-CSF, IL-3, and IL-5. The activated mutant, hbetacFIDelta, is able to confer growth factor-independent proliferation on the murine myeloid cell line FDC-P1, and on primary committed myeloid progenitors. We have used this activating mutation to study the effects of chronic cytokine receptor stimulation. Transgenic mice were produced carrying the hbetacFIDelta cDNA linked to the constitutive promoter derived from the phosphoglycerate kinase gene, PGK-1. Transgene expression was demonstrated in several tissues and functional activity of the mutant receptor was confirmed in hematopoietic tissues by the presence of granulocyte macrophage and macrophage colony-forming cells (CFU-GM and CFU-M) in the absence of added cytokines. All transgenic mice display a myeloproliferative disorder characterized by splenomegaly, erythrocytosis, and granulocytic and megakaryocytic hyperplasia. This disorder resembles the human disease polycythemia vera, suggesting that activating mutations in hbetac may play a role in the pathogenesis of this myeloproliferative disorder. In addition, these transgenic mice develop a sporadic, progressive neurological disease and display bilateral, symmetrical foci of necrosis in the white matter of brain stem associated with an accumulation of macrophages. Thus, chronic hbetac activation has the potential to contribute to pathological events in the central nervous system.
authors.affiliation: The Hanson Centre for Cancer Research, Division of Human Immunology, Adelaide, 5000 South Australia, Australia. Richard.Dandrea@imvs.sa
authors.forename: R J
authors.initials: RJ
authors.lastname: D'Andrea
authors.forename: D
authors.initials: D
authors.lastname: Harrison-Findik
authors.forename: C M
authors.initials: CM
authors.lastname: Butcher
authors.forename: J
authors.initials: J
authors.lastname: Finnie
authors.forename: P
authors.initials: P
authors.lastname: Blumbergs
authors.forename: P
authors.initials: P
authors.lastname: Bartley
authors.forename: M
authors.initials: M
authors.lastname: McCormack
authors.forename: K
authors.initials: K
authors.lastname: Jones
authors.forename: R
authors.initials: R
authors.lastname: Rowland
authors.forename: T J
authors.initials: TJ
authors.lastname: Gonda
authors.forename: M A
authors.initials: MA
authors.lastname: Vadas
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000473:pathology; D002531:Cerebellum / Q000473:pathology; D053648:Cytokine Receptor Common beta Subunit; D016207:Cytokines / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009196:Myeloproliferative Disorders / Q000209:etiology* / Q000235:genetics; D009336:Necrosis; D019636:Neurodegenerative Diseases / Q000209:etiology* / Q000235:genetics; D009857:Oncogenes; D011087:Polycythemia Vera; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D019076:Transgenes
chemical_list: C115876:CSF2RB protein, human; D053648:Cytokine Receptor Common beta Subunit; D016207:Cytokines; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins