文章：

SUMOylation抑制增强多发性骨髓瘤对来那度胺的敏感性

SUMOylation inhibition enhances multiple myeloma sensitivity to lenalidomide 

原文发布日期：2022-03-25 

英文摘要：

Despite the potent effect of lenalidomide (Len) in multiple myeloma (MM) treatment, patients develop Len resistance leading to progressive disease, demanding an urgent need to investigate the mechanisms mediating Len resistance. Our study identified SUMOylation as a potential mechanism regulating Len resistance in MM. Len-resistant MM cell line MMR10R presented much higher SUMO E1 (SAE2) expression and more global SUMOylation than Len-sensitive MM1S cell line. SUMOylation inhibition by using TAK-981, a novel and specific SUMO E1 inhibitor, significantly enhances myeloma sensitivity to Len in MM cell lines. Moreover, the enhanced anti-MM activity by TAK-981 and Len combination has been validated using primary relapsing MM patient samples. Overexpression of IRF4 and c-Myc is a major mechanism of Len resistance. Len showed limited effect on IRF4 and c-Myc level in Len-resistance cell line, but TAK-981 treatment reduced IRF4 and c-Myc expression in Len-resistant line and caused further decrease when combined with Len. We found SUMOylation inhibition decreases IRF4 at transcriptional and post-translational level. SUMOylation inhibition reduced DOT1L with decreased methylation of histone H3 lysine 79, to suppress IRF4 gene transcription. SUMOylation inhibition also reduced IRF4 protein level by enhancing degradation. Overall, our data revealed SUMOylation inhibition enhances Len sensitivity through downregulating IRF4. 

摘要翻译： 

尽管来那度胺（Len）在多发性骨髓瘤（MM）治疗中具有强效作用，患者仍会产生来那度胺耐药性导致疾病进展，亟需探究介导来那度胺耐药性的机制。我们的研究发现SUMO化是调节多发性骨髓瘤来那度胺耐药性的潜在机制。耐药细胞系MMR10R比敏感细胞系MM1S表现出显著更高的SUMO E1（SAE2）表达水平和更广泛的全局SUMO化。通过使用新型特异性SUMO E1抑制剂TAK-981抑制SUMO化，能显著增强多发性骨髓瘤细胞系对来那度胺的敏感性。此外，我们采用原代复发多发性骨髓瘤患者样本验证了TAK-981与来那度胺联用增强的抗骨髓瘤活性。IRF4和c-Myc的过表达是来那度胺耐药的主要机制。在耐药细胞系中，来那度胺对IRF4和c-Myc水平的影响有限，但TAK-981治疗降低了耐药细胞系中IRF4和c-Myc的表达，且与来那度胺联用时可进一步降低。我们发现SUMO化抑制在转录和翻译后水平降低IRF4：通过减少DOT1L及其介导的组蛋白H3赖氨酸79甲基化来抑制IRF4基因转录，同时通过增强降解作用降低IRF4蛋白水平。本研究揭示了SUMO化抑制通过下调IRF4来增强来那度胺敏感性的机制。

原文链接：

SUMOylation inhibition enhances multiple myeloma sensitivity to lenalidomide