文章：

Pim2对调节多发性骨髓瘤细胞中的DNA损伤反应很重要

Pim2 is important for regulating DNA damage response in multiple myeloma cells

原文发布日期：2016-08-26

DOI: 10.1038/bcj.2016.73

类型: Original Article

开放获取: 是

英文摘要：

Pan proviral integrations of Moloney virus (PIM) inhibition in multiple myeloma (MM) results in reduced cell viability in tested human-derived MM cell lines and reduces tumor burden in xenograft mouse models, making PIMs important therapeutic targets for the disease. PIM kinase inhibitors are currently being tested clinically in MM. We sought to elucidate the role of the various PIMs in MM. Our data demonstrate that Pim2 has a significant role in MM cell cytotoxicity. Our data provide evidence for a novel role for Pim2 in the regulation of the DNA damage response (DDR). Knockdown of Pim2 upregulates several downstream DDR markers, mimicking the effects of doxorubicin (Dox) treatment of MM cells, and suggesting a role for the kinase as a negative regulator of this pathway. Dox-induced DNA damage results in a decrease in Pim2 levels, placing the kinase directly downstream of the site of Dox-DNA binding. Overexpression of Pim2 confers a slight survival advantage against Dox through antiapoptotic activity, further underscoring its relevance in the DDR pathway. These data provide insights into a novel mechanism of PIM kinase activity and provide the framework for designing therapeutic approaches in MM.

摘要翻译： 

在多种骨髓瘤（MM）中，抑制潘莫洛尼病毒前病毒整合（PIM）会导致测试的人源MM细胞系细胞活力降低，并在异种移植小鼠模型中减轻肿瘤负荷，这使得PIM成为该疾病的重要治疗靶点。PIM激酶抑制剂目前正在MM中进行临床测试。我们试图阐明各种PIM在MM中的作用。我们的数据表明，Pim2在MM细胞毒性中具有重要作用。这些数据为Pim2在DNA损伤反应（DDR）调控中的新作用提供了证据。敲低Pim2会上调多个下游DDR标志物，模拟多柔比星（Dox）处理MM细胞的效果，表明该激酶是该通路的负调控因子。Dox诱导的DNA损伤会导致Pim2水平下降，将该激酶定位在Dox-DNA结合位点的直接下游。过表达Pim2通过抗凋亡活性赋予对Dox的轻微生存优势，进一步强调了其在DDR通路中的相关性。这些数据揭示了PIM激酶活性的新机制，并为设计MM治疗方法提供了框架。

原文链接：

Pim2 is important for regulating DNA damage response in multiple myeloma cells