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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 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 Citation Map 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. Related Collections Myeloid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA Selective reduction of JAK2V617F-dependent cell growth by siRNA/shRNA and its reversal by cytokines Abire Jedidi13, Caroline Marty13, Charleen Oligo13, Laurence Jeanson-Leh1,3,4, Jean-Antoine Ribeil5, Nicole Casadevall1,6, Anne Galy1,3,4, William Vainchenker13, and Jean-Luc Villeval13 1 Inserm, Unité 790, Institut Gustave Roussy (IGR), Villejuif; 2 IGR, Villejuif; 3 Université Paris XI, Villejuif; 4 Genethon, Evry; 5 Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8147, Faculté de Médecine et Université René Descartes Paris V, Institut Fédérative Necker, Paris; and 6 Assistance Publique–Hôpitaux de Paris, Hôpital Saint-Antoine, Laboratoire d'Hématologie, Paris, France The JAKV617F mutation is responsible for the majority of breakpoint cluster region (BCR)/Abelson (ABL)–negative myeloproliferative disorders. Ongoing clinical trials of Janus kinase 2 (JAK2) inhibitors in myeloproliferative disorder patients use small molecules targeting both wild-type and mutated JAK2. To selectively target malignant cells, we developed JAK2V617F-specific small interfering RNAs or short hairpin RNAs. 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 signal transducer and activator of transcription 5 phosphorylation, cell-cycle progression, and cell survival. However, the addition of high concentrations of cytokines to cell lines or erythropoietin 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 RNA interference (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]

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