Identification of early growth response protein 1 (EGR-1) as a novel target for JUN-induced apoptosis in multiple myeloma
Identification of early growth response protein 1 (EGR-1) as a novel target for JUN-induced apoptosis in multiple myeloma
复制标题
鉴定早期生长反应蛋白 1 (EGR-1) 作为 JUN 诱导多发性骨髓瘤细胞凋亡的新靶标
DOI：
10.1182/blood-2009-03-210526
复制
发表时间：
2010-01-07
期刊：
影响因子：
20.3
通讯作者：
Zhan, Fenghuang
中科院分区：
文献类型：
--
作者：
Chen, Lijuan;Wang, Siqing;Zhan, Fenghuang
多发性骨髓瘤（MM）中的肿瘤-骨髓微环境相互作用被证明在浆细胞生长/存活中起关键作用。在体外共培养的MM细胞与破骨细胞支持细胞的生存和显着下调JUN的表达。晚期和高危MM的骨髓瘤细胞中的JUN表达显著低于健康供体、意义不明的单克隆丙种球蛋白病、郁积型MM和低危MM的浆细胞;低JUN表达MM细胞的患者有较早的疾病相关死亡。JUN在MM细胞中的过表达诱导细胞死亡和生长抑制，并上调早期生长反应蛋白1（EGR-1）的表达，EGR-1的低表达也具有不利的临床意义。在MM细胞中，EGR-1敲低消除了JUN过表达诱导的MM细胞死亡和生长抑制，表明EGR-1直接作用于JUN的下游JUN通过与EGR-1相互作用调节骨髓瘤细胞凋亡，EGR-1下调Survivin并触发caspase信号传导。重要的是，高JUN或EGR-1表达与总体治疗3中的改善结果相关，其中在整个治疗过程中给予硼替佐米，而总体治疗2中仅在复发时给予硼替佐米。一致地，在培养的MM细胞中JUN或EGR-1敲低增强了它们对硼替佐米的抗性，证明了低JUN/EGR-1表达在MM对硼替佐米的抗性中的关键作用。（血。2010;115：61-70）
Tumor-bone marrow microenvironment interactions in multiple myeloma (MM) are documented to play crucial roles in plasma-cell growth/survival. In vitro coculture of MM cells with osteoclasts supported cell survival and significantly down-regulated JUN expression. JUN expression in myeloma cells from late-stage and high-risk MM was significantly lower than in plasma cells from healthy donors, monoclonal gammopathy of undetermined significance, smoldering MM, and low-risk MM; patients with low-JUN-expressing MM cells had earlier disease-related deaths. JUN overexpression in MM cells induced cell death and growth inhibition and up-regulated expression of early growth response protein 1 (EGR-1), whose low expression also carried unfavorable clinical implications. EGR-1 knockdown in MM cells abrogated JUN overexpression-induced MM cell death and growth inhibition, indicating that EGR-1 acts directly downstream of JUN. JUN modulates myeloma cell apoptosis through interacting with EGR-1, which down-regulates Survivin and triggers caspase signaling. Importantly, high JUN or EGR-1 expression was associated with improved outcome in Total Therapy 3, in which bortezomib is given throughout therapy, versus Total Therapy 2, in which bortezomib is given only at relapse. Consistently, JUN or EGR-1 knockdown in cultured MM cells enhanced their resistance to bortezomib, demonstrating the crucial role of low JUN/EGR-1 expression in MM resistance to bortezomib. (Blood. 2010;115:61-70)