文章：

在接受硼替佐米联合地塞米松治疗的多发性骨髓瘤患者中，转录激活因子3和4的低表达与更短的无进展生存期相关

Lower expression of activating transcription factors 3 and 4 correlates with shorter progression-free survival in multiple myeloma patients receiving bortezomib plus dexamethasone therapy

原文发布日期：2015-12-04

DOI: 10.1038/bcj.2015.98

类型: Original Article

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英文摘要：

Bortezomib (BTZ), a proteasome inhibitor, is widely used in the treatment of multiple myeloma (MM), but a fraction of patients respond poorly to this agent. To identify factors predicting the duration of progression-free survival (PFS) of MM patients on BTZ treatment, the expression of proteasome and endoplasmic reticulum (ER) stress-related genes was quantified in primary samples from patients receiving a combination of BTZ and dexamethasone (BD). Fifty-six MM patients were stratified into a group with PFS<6 months (n=33) and a second group with PFS⩾6 months (n=23). Of the 15 genes analyzed, the expression of activating transcription factor 3 (ATF3) and ATF4 was significantly lower in patients with shorter PFS (P=0.0157 and P=0.0085, respectively). Chromatin immunoprecipitation analysis showed that these ATFs bind each other and transactivate genes encoding the pro-apoptotic transcription factors, CHOP and Noxa, which promote ER stress-associated apoptosis. When either ATF3 or ATF4 expression was silenced, MM cells partially lost sensitivity to BTZ treatment. This was accompanied by lower levels of Noxa, CHOP and DR5. Thus low basal expression of ATF3 and ATF4 may attenuate BTZ-induced apoptosis. Hence, ATF3 and ATF4 could potentially be used as biomarkers to predict efficacy of BD therapy in patients with MM.

摘要翻译： 

硼替佐米（BTZ）是一种蛋白酶体抑制剂，广泛用于多发性骨髓瘤（MM）的治疗，但部分患者对该药物反应不佳。为识别预测BTZ治疗MM患者无进展生存期（PFS）的因素，本研究在接受BTZ与地塞米松联合疗法（BD）的患者原代样本中量化了蛋白酶体及内质网（ER）应激相关基因的表达。56例MM患者被分为PFS<6个月组（33例）和PFS≥6个月组（23例）。在分析的15个基因中，激活转录因子3（ATF3）和ATF4的表达在PFS较短患者中显著降低（分别为P=0.0157和P=0.0085）。染色质免疫沉淀分析显示，这些ATF相互结合并反式激活编码促凋亡转录因子CHOP和Noxa的基因，这些因子促进ER应激相关凋亡。当沉默ATF3或ATF4表达时，MM细胞对BTZ治疗的敏感性部分降低，同时伴随Noxa、CHOP和DR5水平下降。因此，ATF3和ATF4的低基础表达可能减弱BTZ诱导的凋亡。这表明ATF3和ATF4有望作为预测BD疗法对MM患者疗效的生物标志物。

原文链接：

Lower expression of activating transcription factors 3 and 4 correlates with shorter progression-free survival in multiple myeloma patients receiving bortezomib plus dexamethasone therapy