Philadelphia negative (Ph-neg) myeloproliferative neoplasms (MPN) are a heterogenous group of clonal stem cell disorders. Approved treatment options include hydroxyurea, anagrelide, and ruxolitinib, which are not curative. The concept of synthetic lethality may become an additional therapeutic strategy in these diseases. In our study, we show that DNA repair is altered in classical Ph-neg MPN, as analyzed by gene expression analysis of 11 genes involved in the homologous recombination repair pathway (HRR), the non-homologous end-joining pathway (NHEJ), and the single-strand break repair pathway (SSB). Altogether, peripheral blood-derived cells from 57 patients with classical Ph-neg MPN and 13 healthy controls were analyzed. LIG3 as an essential part of the SSB was significantly lower expressed compared to controls in all three entities (essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF)). In addition, while genes of other DNA-repair pathways showed-possibly compensatory-increased expression in ET (HRR, NHEJ) and PV (NHEJ), MF samples displayed downregulation of all genes involved in NHEJ. With regard to the JAK2 mutational status (analyzed in ET and MF only), no upregulation of the HRR was detected. Though further studies are needed, based on these findings, we conclude that synthetic lethality may become a promising strategy in treating patients with Ph-neg MPN.

中文翻译：

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费城染色体阴性骨髓增生性肿瘤中DNA修复基因的转录改变。

费城阴性（Ph-neg）骨髓增生性肿瘤（MPN）是一组异源性克隆干细胞疾病。批准的治疗选择包括非治愈性的羟基脲，阿那格雷和鲁索替尼。合成杀伤力的概念可能会成为这些疾病的另一种治疗策略。在我们的研究中，我们通过对11个参与同源重组修复途径（HRR），非同源末端连接途径（NHEJ）的基因进行基因表达分析，发现经典Ph-neg MPN中的DNA修复发生了变化，以及单链断裂修复途径（SSB）。总共分析了57例经典Ph-neg MPN患者和13例健康对照者的外周血来源细胞。与所有三个实体（必需性血小板增多症（ET），真性红细胞增多症（PV）和骨髓纤维化（MF））相比，LIG3作为SSB的重要组成部分的表达水平明显低于对照组。此外，尽管其他DNA修复途径的基因在ET（HRR，NHEJ）和PV（NHEJ）中表达可能补偿性增加，但MF样品显示与NHEJ相关的所有基因均下调。关于JAK2突变状态（仅在ET和MF中进行了分析），未检测到HRR的上调。尽管需要进一步的研究，但基于这些发现，我们得出结论，合成杀伤力可能成为治疗Ph-neg MPN患者的有前途的策略。尽管其他DNA修复途径的基因在ET（HRR，NHEJ）和PV（NHEJ）中表达可能补偿性增加，但MF样品显示与NHEJ相关的所有基因均下调。关于JAK2突变状态（仅在ET和MF中进行了分析），未检测到HRR的上调。尽管需要进一步的研究，但基于这些发现，我们得出结论，合成杀伤力可能成为治疗Ph-neg MPN患者的有前途的策略。尽管其他DNA修复途径的基因在ET（HRR，NHEJ）和PV（NHEJ）中表达可能补偿性增加，但MF样品显示与NHEJ相关的所有基因均下调。关于JAK2突变状态（仅在ET和MF中进行了分析），未检测到HRR的上调。尽管需要进一步的研究，但基于这些发现，我们得出结论，合成杀伤力可能成为治疗Ph-neg MPN患者的有前途的策略。