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Blood, 15 August 2008, Vol. 112, No. 4, pp. 1402-1412. Prepublished online as a Blood First Edition Paper on May 30, 2008; DOI 10.1182/blood-2008-01-134114. This Article Full Text (PDF) All Versions of this Article: blood-2008-01-134114v1 112/4/1402    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 Citing Articles via Google Scholar Google Scholar Articles by Plo, I. Articles by Vainchenker, W. Search for Related Content PubMed PubMed Citation Articles by Plo, I. Articles by Vainchenker, W. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 15, 2008 Accepted May 12, 2008 JAK2 stimulates homologous recombination and genetic instability : potential implication in the heterogeneity of myeloproliferative disorders Isabelle Plo, Mayuka Nakatake, Laurent Malivert, Jean-Pierre de Villartay, Stephane Giraudier, Jean-Luc Villeval, Lisa Wiesmuller, and William Vainchenker* INSERM, UMR790, Villejuif, France Universite Paris XI, UMR790, Institut Gustave Roussy, Villejuif, France INSERM, U768, Hopital Necker-Enfants Malades, Paris, France Institut Gustave Roussy, Villejuif, France Department of Obstetrics and Gynaecology of the University of Ulm, Ulm, Germany * Corresponding author; email: verpre{at}igr.fr. The JAK2V617F mutation is frequently observed in classical myeloproliferative disorders and disease progression is associated with a bi-allelic acquisition of the mutation occurring by mitotic recombination. In this study, we examined whether JAK2 activation could lead to increased homologous recombination (HR) and genetic instability. In a Ba/F3 cell line expressing the erythropoietin (EPO) receptor, mutant JAK2V617F and, to a lesser extent, wild type (wt) JAK2 induced an increase in HR activity in the presence of EPO without modifying NHEJ efficiency. Moreover, a marked augmentation in HR activity was found in CD34+ derived cells isolated from patients with Polycythemia Vera or Primitive myelofibrosis in comparison to control samples. This increase was associated with a spontaneous RAD51 foci formation. As a result, sister chromatid exchange was 50% augmented in JAK2V617F Ba/F3 cells compared to JAK2wt cells. Moreover, JAK2 activation increased centrosome and ploidy abnormalities. Finally, in JAK2V617F, Ba/F3 cells, we found a 100-fold and 10-fold increase in mutagenesis at the HPRT and Na/K ATPase loci, respectively. Together, this work highlights a new molecular mechanism for HR regulation mediated by JAK2 and more efficiently by JAK2V617F. Our study might provide some keys to understand how a single mutation can give rise to different pathologies. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. He and Y. Zhang Janus Kinase 2: An Epigenetic 'Writer' that Activates Leukemogenic Genes J Mol Cell Biol, January 5, 2010; (2010) mjp054v1. [Abstract] [Full Text] [PDF] Y. Wang, W. Fiskus, D. G. Chong, K. M. Buckley, K. Natarajan, R. Rao, A. Joshi, R. Balusu, S. Koul, J. Chen, et al. Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells Blood, December 3, 2009; 114(24): 5024 - 5033. [Abstract] [Full Text] [PDF] A. M. Vannucchi, G. Masala, E. Antonioli, M. Chiara Susini, P. 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