MIF as a biomarker and therapeutic target for overcoming resistance to proteasome inhibitors in human myeloma.
MIF as a biomarker and therapeutic target for overcoming resistance to proteasome inhibitors in human myeloma.
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DOI：
10.1182/blood.2020005795
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发表时间：
2020-06
期刊：
影响因子：
20.3
通讯作者：
Qiang Wang;Dongyu Zhao;M. Xian;Zhuo Wang;Enguang Bi;Pan Su;J. Qian;Xingzhe Ma;Maojie Yang;Lintao Liu;Y. Zu;S. Pingali;Kaifu Chen;Z. Cai;Q. Yi
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文献类型：
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作者：
Qiang Wang;Dongyu Zhao;M. Xian;Zhuo Wang;Enguang Bi;Pan Su;J. Qian;Xingzhe Ma;Maojie Yang;Lintao Liu;Y. Zu;S. Pingali;Kaifu Chen;Z. Cai;Q. Yi
尽管生物和化疗取得了显着进展，多发性骨髓瘤（MM）在很大程度上仍然无法治愈。MM管理的主要问题是耐药性的发展。复发患者纯化的MM细胞中巨噬细胞移动抑制因子（MIF）表达显著高于持续缓解患者，高MIF MM患者的无进展生存期（PFS）和总生存期（OS）显著缩短。MM细胞系也表达高水平的MIF，并且敲除MIF使它们对蛋白酶体抑制剂（PI）诱导的细胞凋亡更敏感，而其他化疗药物未观察到。机制研究表明，MIF保护MM细胞免受PI诱导的凋亡，通过抑制PI引起的超氧化物产生来维持线粒体功能。具体而言，MIF以同源三聚体的形式充当超氧化物歧化酶1（SOD 1）的伴侣，以抑制PI诱导的SOD 1错误折叠并维持SOD 1活性。MIF抑制剂4-IPP和同源三聚体破坏剂依布硒啉（不杀死MM细胞）增强了PI诱导的SOD 1错误折叠和功能丧失，导致细胞系和原代MM细胞中显著更多的细胞死亡。更重要的是，在体内抑制MIF活性显示出与PI的协同抗肿瘤活性，并使PI耐药MM细胞对治疗重新敏感。为了支持这些发现，基因分析数据显示MM患者中MIF和SOD 1表达与PI治疗反应之间存在显著负相关性。因此，这项研究表明，MIF在MM对PI的敏感性中起着至关重要的作用，并表明靶向MIF可能是一种有前途的策略，可以使MM对治疗（重新）敏感。
Multiple myeloma (MM) remains largely incurable despite significant advances in bio- and chemotherapy. The major problem in MM management is development of drug resistance. Macrophage migration inhibitory factor (MIF) expression was significantly higher in purified MM cells from relapsed patients than those with sustained response, and high MIF MM patients had significantly shorter progression-free survival (PFS) and overall survival (OS). MM cell lines also express high levels of MIF, and knocking out MIF made them more sensitive to proteasome inhibitor (PI) induced apoptosis not observed with other chemotherapy drugs. Mechanistic studies showed that MIF protects MM cells from PI-induced apoptosis by maintaining mitochondrial function via suppression of superoxide production in response to PIs. Specifically, MIF, in the form of a homotrimer, acts as a chaperone for superoxide dismutase 1 (SOD1) to suppress PI-induced SOD1 misfolding and maintain SOD1 activity. MIF inhibitor 4-IPP and homotrimer disrupter ebselen, which do not kill MM cells, enhanced PI-induced SOD1 misfolding and loss of function, resulting in significantly more cell death in both cell lines and primary MM cells. More importantly, inhibiting MIF activity in vivo displayed synergistic antitumor activity with PIs and re-sensitized PI-resistant MM cells to treatment. In support of these findings, gene-profiling data showed a significantly negative correlation between MIF and SOD1 expression and response to PI treatment in MM patients. Hence, this study reveals that MIF plays a crucial role in MM sensitivity to PIs, and suggests that targeting MIF may be a promising strategy to (re)sensitize MM to the treatment.