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J. Biol. Chem., Vol. 281, Issue 26, 18177-18183, June 30, 2006

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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^¶, and Martin Sattler^¶1

From the Department of Medical Oncology, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and ^¶Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

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 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 G₁/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 G₁/S phase transition downstream of Jak2V617F/STAT5 and therefore hint at potential novel targets for drug development that may aid traditional therapy.

Received for publication, January 4, 2006 , and in revised form, April 21, 2006.

^* This work was supported by the Landesstiftung Baden-Württemberg (to C. W.), National Institutes of Health Grant DK66996, a Leukemia and Lymphoma Society SCOR grant (to J. D. G.), and an American Cancer Society Research Scholar grant (to M. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115. Tel.: 617-632-4382; Fax: 617-632-4388; E-mail: martin_sattler{at}dfci.harvard.edu.

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