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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 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 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 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. Related Collections Hematopoiesis and Stem Cells Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA JAK2 stimulates homologous recombination and genetic instability: potential implication in the heterogeneity of myeloproliferative disorders Isabelle Plo13, Mayuka Nakatake13, Laurent Malivert4, Jean-Pierre de Villartay4, Stéphane Giraudier13, Jean-Luc Villeval13, Lisa Wiesmuller5, and William Vainchenker13 1 Inserm, Unités mixtes de recherche (UMR) 790, Villejuif, France; 2 Université Paris XI, UMR790, Institut Gustave Roussy, Villejuif, France; 3 Institut Gustave Roussy, Villejuif, France; 4 Inserm, U768, Hôpital Necker-Enfants Malades, Paris, France; and 5 Department of Obstetrics and Gynaecology of the University of Ulm, Ulm, Germany The JAK2V617F mutation is frequently observed in classical myeloproliferative disorders, and disease progression is associated with a biallelic 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 nonhomologous end-joining efficiency. Moreover, a marked augmentation in HR activity was found in CD34+-derived cells isolated from patients with polycythemia vera or primitive myelofibrosis compared with 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 with 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: A. M. Vannucchi, G. Masala, E. Antonioli, M. Chiara Susini, P. Guglielmelli, L. Pieri, L. Maggi, S. Caini, D. Palli, C. Bogani, et al. Increased Risk of Lymphoid Neoplasms in Patients with Philadelphia Chromosome-Negative Myeloproliferative Neoplasms Cancer Epidemiol. Biomarkers Prev., July 1, 2009; 18(7): 2068 - 2073. [Abstract] [Full Text] [PDF] F. Colotta, P. Allavena, A. Sica, C. Garlanda, and A. Mantovani Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability Carcinogenesis, July 1, 2009; 30(7): 1073 - 1081. [Abstract] [Full Text] [PDF] F. X. Schaub, R. Jager, R. Looser, H. Hao-Shen, S. Hermouet, F. Girodon, A. Tichelli, H. Gisslinger, R. Kralovics, and R. C. Skoda Clonal analysis of deletions on chromosome 20q and JAK2-V617F in MPD suggests that del20q acts independently and is not one of the predisposing mutations for JAK2-V617F Blood, February 26, 2009; 113(9): 2022 - 2027. [Abstract] [Full Text] [PDF] R. Zhao, G. A. Follows, P. A. Beer, L. M. Scott, B. J.P. Huntly, A. R. Green, and D. R. Alexander Inhibition of the Bcl-xL Deamidation Pathway in Myeloproliferative Disorders N. Engl. J. Med., December 25, 2008; 359(26): 2778 - 2789. [Abstract] [Full Text] [PDF]

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