JAK2 stimulates homologous recombination and genetic instability: potential implication in the heterogeneity of myeloproliferative disorders
JAK2 stimulates homologous recombination and genetic instability: potential implication in the heterogeneity of myeloproliferative disorders
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DOI：
10.1182/blood-2008-01-134114
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发表时间：
2008-08-15
期刊：
影响因子：
20.3
通讯作者：
Vainchenker, William
中科院分区：
文献类型：
--
作者：
Plo, Isabelle;Nakatake, Mayuka;Vainchenker, William
JAK 2（V617 F）突变经常在经典的骨髓增生性疾病中观察到，疾病进展与有丝分裂重组发生的突变的双等位基因获得相关。在这项研究中，我们研究了JAK 2激活是否会导致同源重组（HR）和遗传不稳定性增加。在表达促红细胞生成素（EPO）受体的Ba/F3细胞系中，突变体JAK 2（V617 F）和在较小程度上野生型（wt）JAK 2在EPO存在下诱导HR活性增加，而不改变非同源末端连接效率。此外，与对照组相比，从真性红细胞增多症或原发性骨髓纤维化患者分离的CD 34（+）衍生细胞中发现HR活性显著增强。这种增加与自发性RAD 51灶形成有关。结果，与JAK 2 wt细胞相比，JAK 2（V617 F）Ba/F3细胞中的姐妹染色单体交换增加了50%。此外，JAK 2激活增加了中心体和倍性异常。最后，在JAK 2（V617 F）Ba/F3细胞中，我们发现HPRT和Na/K ATP酶位点的诱变分别增加了100倍和10倍。总之，这项工作突出了JAK 2介导的HR调节的新分子机制，并且JAK 2 V617 F更有效。我们的研究可能会提供一些关键，以了解如何一个单一的突变可以引起不同的病理。
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 JAK2V617F. Our study might provide some keys to understand how a single mutation can give rise to different pathologies.