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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.
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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.
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