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Papers In Press, published online ahead of print April 21, 2006
Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115
Corresponding Author: martin_sattler{at}dfci.harvard.edu
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 G1 cell cycle arrest. This inhibition correlated with decreased expression of cyclin D2 and increased expression of the cell cycle inhibitor p27Kip. Inhibition of Jak2V617F with a Jak2-targeted siRNA approach resulted in a similar phenotype. Mechanisms leading to altered p27Kip and cyclin D2 likely involve inhibition of STAT5, a major target of Jak2 in hematopoietic cells, since a constitutively active form of STAT5 reduced p27Kip and increased cyclin D2 expression. Jak2V617F and constitutively active STAT5 also induced high levels of reactive oxygen species (ROS), which are sufficient to promote G1/S-phase transition. In contrast, treatment of HEL cells with the anti-oxidant N-acetylcysteine decreased cell growth or expression of cyclin D2 and increased expression of p27Kip. 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 p27Kip in combination with redox-dependent processes promotes G1/S-phase transition downstream of Jak2V617F/STAT5 and therefore hint at potential novel targets for drug development that may aid traditional therapy.
J. Biol. Chem, 10.1074/jbc.M600064200
Submitted on January 4, 2006
Revised on April 21, 2006
Accepted on April 21, 2006
Activated JAK2 with the V617F point mutation promotes G1/S-phase transition
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