Activated Jak2 with the V617F point mutation promotes G1/S phase transition

Christoph Walz, Brian J Crowley, Heidi E Hudon, Jessica L Gramlich, Donna S Neuberg, Klaus Podar, James D Griffin, Martin Sattler

Research output: Journal article (peer-reviewed)Journal article

92 Citations (Scopus)

Abstract

Hematopoietic stem cells in myeloproliferative diseases mostly retain the potential to differentiate but are characterized by hyper-responsiveness to growth factors, as well as partial factor-independent growth. The V617F activating point mutation in Jak2 has recently been associated with myeloproliferative disorders. Using various cell line models, mechanisms that contribute to Jak2V617-mediated signaling were investigated. Treatment of the Jak2V617F mutant-expressing erythroid leukemia cell line HEL with a small molecule Jak2 inhibitor was associated with a dose-dependent G(1) cell cycle arrest. This inhibition correlated with decreased expression of cyclin D2 and increased expression of the cell cycle inhibitor p27(Kip). Inhibition of Jak2V617F with a Jak2-targeted small interfering RNA approach resulted in a similar phenotype. Mechanisms leading to altered p27(Kip) and cyclin D2 likely involve inhibition of STAT5, a major target of Jak2 in hematopoietic cells, because a constitutively active form of STAT5 reduced p27(Kip) and increased cyclin D2 expression. Jak2V617F and constitutively active STAT5 also induced high levels of reactive oxygen species, which are sufficient to promote G(1)/S phase transition. In contrast, treatment of HEL cells with the antioxidant N-acetylcysteine decreased cell growth or expression of cyclin D2 and increased expression of p27(Kip). Similar results were obtained in BaF3 cells transfected with Jak2V617F, but these cells required coexpression of the erythropoietin receptor for optimal signaling. These results suggest that regulation of cyclin D2 and p27(Kip) in combination with redox-dependent processes promotes G(1)/S phase transition downstream of Jak2V617F/STAT5 and therefore hint at potential novel targets for drug development that may aid traditional therapy.

Original languageEnglish
Pages (from-to)18177-18183
Number of pages7
JournalJournal of Biological Chemistry
Volume281
Issue number26
DOIs
Publication statusPublished - 30 Jun 2006
Externally publishedYes

Keywords

  • Apoptosis/physiology
  • Cell Transformation, Neoplastic
  • Cyclin D2
  • Cyclin-Dependent Kinase Inhibitor p27/metabolism
  • Cyclins/metabolism
  • G1 Phase/physiology
  • Gene Expression Regulation, Leukemic
  • Humans
  • Janus Kinase 2
  • K562 Cells
  • Leukemia, Erythroblastic, Acute/genetics
  • Oxidation-Reduction
  • Point Mutation
  • Protein-Tyrosine Kinases/genetics
  • Proto-Oncogene Proteins/genetics
  • Pyridones/metabolism
  • Receptors, Erythropoietin/metabolism
  • S Phase/physiology
  • STAT5 Transcription Factor/metabolism

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