JAK2 stimulates homologous recombination and genetic instability: potential implication in the heterogeneity of myeloproliferative disorders

Blood. 2008 Aug 15;112(4):1402-12. doi: 10.1182/blood-2008-01-134114. Epub 2008 May 30.

Abstract

The JAK2(V617F) 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 JAK2(V617F) 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 JAK2(V617F) Ba/F3 cells compared with JAK2wt cells. Moreover, JAK2 activation increased centrosome and ploidy abnormalities. Finally, in JAK2(V617F) 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 JAK2(V617F). Our study might provide some keys to understand how a single mutation can give rise to different pathologies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Humans
  • Hypoxanthine Phosphoribosyltransferase / genetics
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / physiology*
  • Mice
  • Mutation, Missense
  • Myeloproliferative Disorders / genetics*
  • Myeloproliferative Disorders / pathology
  • Polycythemia Vera / genetics
  • Primary Myelofibrosis / genetics
  • Recombination, Genetic*
  • Sodium-Potassium-Exchanging ATPase / genetics
  • Tumor Cells, Cultured

Substances

  • Hypoxanthine Phosphoribosyltransferase
  • Janus Kinase 2
  • Sodium-Potassium-Exchanging ATPase