SEARCH:   Advanced

Blood, 27 August 2009, Vol. 114, No. 9, pp. 1842-1851. Prepublished online as a Blood First Edition Paper on July 9, 2009; DOI 10.1182/blood-2008-09-176875. This Article Full Text (PDF) All Versions of this Article: blood-2008-09-176875v1 114/9/1842    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Google Scholar Articles by Jedidi, A. Articles by Villeval, J.-L. PubMed PubMed Citation Articles by Jedidi, A. Articles by Villeval, J.-L. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 9, 2008 Accepted May 10, 2009 Selective reduction of JAK2V617F-dependent cell growth by siRNA / shRNA and its reversal by cytokines Abire Jedidi, Caroline Marty, Charleen Oligo, Laurence Jeanson-Leh, Jean-Antoine Ribeil, Nicole Casadevall, Anne Galy, William Vainchenker, and Jean-Luc Villeval* Inserm, U790, Institut Gustave Roussy (IGR), Villejuif, France Institut Gustave Roussy, Villejuif, France Universite Paris XI, Villejuif, France Genethon, Evry, France CNRS, UMR 8147, Faculte de Medecine et Universite Rene Descartes Paris V, Institut Federative Necker, Paris, France AP-HP, Hopital Saint-Antoine, Laboratoire d'Hematologie, Paris, France * Corresponding author; email: villeval{at}igr.fr. The JAKV617F mutation is responsible for the majority of BCR/ABL-negative myeloproliferative disorders (MPD). Ongoing clinical trials of JAK2 inhibitors in MPD patients use small molecules targeting both wild type and mutated JAK2. In order to selectively target malignant cells, we developed JAK2V617F-specific small interfering RNAs (siRNAs) or short hairpin RNAs (shRNAs). Expression of these RNAs in cell lines or CD34+ cells from patients reduced JAK2V617F-driven autonomous cell proliferation. Mechanisms of inhibition involved selective JAK2V617F protein down-regulation and consequently decrease in Stat5 phosphorylation, cell cycle progression and cell survival. However, the addition of high concentrations of cytokines to cell lines or EPO to patient cells greatly reduced growth inhibition. Similarly, the efficacy of a JAK2 small molecule inhibitor on cell line and patient cell proliferation dose-dependently decreased with the addition of cytokines. Our results demonstrate that it is possible to specifically target JAK2V617F by RNAi strategies. In addition, cytokines partially reverse the inhibition induced by both RNAi and small molecule approaches. This strongly suggests that patient cytokine levels in current JAK2 inhibitor clinical trials modulate the outcome of these therapies. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. C.C. Liu, E. Caulder, J. Li, P. Waeltz, A. Margulis, R. Wynn, M. Becker-Pasha, Y. Li, E. Crowgey, G. Hollis, et al. Combined Inhibition of Janus Kinase 1/2 for the Treatment of JAK2V617F-Driven Neoplasms: Selective Effects on Mutant Cells and Improvements in Measures of Disease Severity Clin. Cancer Res., November 15, 2009; 15(22): 6891 - 6900. [Abstract] [Full Text] [PDF]

	Copyright © 2009 by American Society of Hematology         Online ISSN: 1528-0020