文章：

EZH2在多发性骨髓瘤中的高表达与预后不良及细胞周期调控紊乱相关

Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control

原文发布日期：2017-03-31

DOI: 10.1038/bcj.2017.27

类型: Original Article

开放获取: 是

英文摘要：

Myeloma is heterogeneous at the molecular level with subgroups of patients characterised by features of epigenetic dysregulation. Outcomes for myeloma patients have improved over the past few decades except for molecularly defined high-risk patients who continue to do badly. Novel therapeutic approaches are, therefore, required. A growing number of epigenetic inhibitors are now available including EZH2 inhibitors that are in early-stage clinical trials for treatment of haematological and other cancers with EZH2 mutations or in which overexpression has been correlated with poor outcomes. For the first time, we have identified and validated a robust and independent deleterious effect of high EZH2 expression on outcomes in myeloma patients. Using two chemically distinct small-molecule inhibitors, we demonstrate a reduction in myeloma cell proliferation with EZH2 inhibition, which leads to cell cycle arrest followed by apoptosis. This is mediated via upregulation of cyclin-dependent kinase inhibitors associated with removal of the inhibitory H3K27me3 mark at their gene loci. Our results suggest that EZH2 inhibition may be a potential therapeutic strategy for the treatment of myeloma and should be investigated in clinical studies.

摘要翻译： 

骨髓瘤在分子水平上具有异质性，其中部分亚组患者以表观遗传失调为特征。过去几十年间，骨髓瘤患者的治疗结局已有所改善，但分子定义的高危患者群体仍预后不良。因此，需要探索新的治疗策略。目前表观遗传抑制剂的数量日益增多，包括EZH2抑制剂——该抑制剂正处于早期临床试验阶段，用于治疗携带EZH2突变或过表达且过表达与不良预后相关的血液系统肿瘤及其他癌症。我们首次发现并验证了EZH2高表达对骨髓瘤患者预后的显著且独立的有害影响。通过使用两种化学结构各异的小分子抑制剂，我们证实抑制EZH2可降低骨髓瘤细胞增殖能力，引发细胞周期阻滞并最终导致细胞凋亡。这一机制是通过细胞周期蛋白依赖性激酶抑制因子的上调实现的，该过程伴随着其基因位点抑制性标记H3K27me3的消除。我们的研究结果表明，EZH2抑制可能成为治疗骨髓瘤的潜在治疗策略，值得进行临床研究探索。

原文链接：

Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control