JAK2 stimulates homologous recombination and genetic instability: potential implication in the heterogeneity of myeloproliferative disorders.
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.
Plo
Isabelle
I
Inserm, Unités Mixtes de Recherche 790, Villejuif, France.
Nakatake
Mayuka
M
Malivert
Laurent
L
de Villartay
Jean-Pierre
JP
Giraudier
Stéphane
S
Villeval
Jean-Luc
JL
Wiesmuller
Lisa
L
Vainchenker
William
W
D000818:Animals; D002460:Cell Line; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D053614:Janus Kinase 2 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D020125:Mutation, Missense; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000473:pathology; D011087:Polycythemia Vera / Q000235:genetics; D055728:Primary Myelofibrosis / Q000235:genetics; D011995:Recombination, Genetic; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics; D014407:Tumor Cells, Cultured
D007041:Hypoxanthine Phosphoribosyltransferase; D053614:Janus Kinase 2; D000254:Sodium-Potassium-Exchanging ATPase