Center for Translational Research in Hematological Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston, TX.
Center for Bioinformatics and Computational Biology and.
Blood. 2020 Nov 26;136(22):2557-2573. doi: 10.1182/blood.2020005795.
Multiple myeloma (MM) remains largely incurable despite significant advances in biotherapy and chemotherapy. The development of drug resistance is a major problem in MM management. Macrophage migration inhibitory factor (MIF) expression was significantly higher in purified MM cells from relapsed patients than those with sustained response, and MM patients with high MIF 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 to maintain SOD1 activity. MIF inhibitor 4-iodo-6-phenylpyrimidine 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 resensitized 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 patients with MM. This study shows 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.
多发性骨髓瘤（MM）尽管在生物治疗和化疗方面取得了重大进展，但仍然难以治愈。耐药性的发展是 MM 治疗中的一个主要问题。与持续缓解的患者相比，复发患者的纯化 MM 细胞中巨噬细胞移动抑制因子（MIF）的表达明显更高，并且 MIF 水平高的 MM 患者的无进展生存期（PFS）和总生存期（OS）明显缩短。MM 细胞系也表达高水平的 MIF，敲除 MIF 可使它们对蛋白酶体抑制剂（PI）诱导的凋亡更敏感，而其他化疗药物则没有观察到这种现象。机制研究表明，MIF 通过抑制对 PIs 的超氧化物产生来维持线粒体功能，从而保护 MM 细胞免受 PI 诱导的凋亡。具体而言，三聚体形式的 MIF 作为超氧化物歧化酶 1（SOD1）的伴侣，抑制 PI 诱导的 SOD1 错误折叠并维持 SOD1 活性。MIF 抑制剂 4-碘-6-苯嘧啶和三聚体破坏剂 ebselen 不会杀死 MM 细胞，但会增强 PI 诱导的 SOD1 错误折叠和功能丧失，导致两种细胞系和原代 MM 细胞的细胞死亡明显增加。更重要的是，体内抑制 MIF 活性与 PI 显示出协同的抗肿瘤活性，并使 PI 耐药的 MM 细胞重新对治疗敏感。支持这些发现的是，基因谱数据显示 MIF 与 SOD1 表达之间存在显著的负相关，并且与 MM 患者对 PI 治疗的反应相关。这项研究表明 MIF 在 MM 对 PI 的敏感性中起关键作用，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。
