title: [Analysis of the mechanism of polycythemia vera by studying JAK2 mutant-induced signaling pathway].
abstract: It has been well established that disruption of JAK2 signaling regulation is involved in various hematopoietic disorders; however, the detailed mechanism by which abnormal activation of JAK2 exhibits transforming activity remains to be elucidated. The somatic JAK2 mutation (V617F) was identified in most patients with polycythemia vera (PV). Here, we show that JAK2 V617F mutant was constitutively active and exhibited tumorigenesis activity as a potent oncogene when erythropoietin receptor (EpoR) was co-expressed. To clarify the signaling pathway of JAK2 V617F mutant, we investigated the functional role of downstream transcription factor STAT5 in its induced cellular transformation and tumorigenesis in nude mice. Interestingly, JAK2 V617F mutant failed to exhibit transforming activity when STAT5 activation was inhibited utilizing EpoR mutant (HM). Furthermore, the expression of constitutively active STAT5 mutant (1*6) exhibited transforming activity. Taking these observations together, it is concluded STAT5 plays an essential role in EpoR-JAK2 V617F mutant-induced hematopoietic disorder and would be a good target for the treatment of PV.
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Keio University, Tokyo, Japan. tago-mg@pha.keio.ac.jp
authors.forename: Megumi
authors.initials: M
authors.lastname: Funakoshi-Tago
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D017354:Point Mutation; D011087:Polycythemia Vera / Q000235:genetics* / Q000628:therapy; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000502:physiology; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology*
chemical_list: D017467:Receptors, Erythropoietin; D050799:STAT5 Transcription Factor; C507924:JAK2 protein, human; D053614:Janus Kinase 2