Toni Stephenson Lymphoma Center, Beckman Research Institute of City of Hope, Duarte, CA, USA.
Judy and Bernard Briskin Center for Multiple Myeloma Research, Beckman Research Institute of City of Hope, Duarte, CA, USA.
Cancer Gene Ther. 2023 Apr;30(4):567-574. doi: 10.1038/s41417-022-00450-9. Epub 2022 Mar 25.
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.
尽管来那度胺（Len）在多发性骨髓瘤（MM）治疗中具有强大的作用，但患者会产生 Len 耐药性，导致疾病进展，因此迫切需要研究介导 Len 耐药性的机制。我们的研究发现，SUMO 化修饰是调节 MM 中 Len 耐药性的一种潜在机制。与 Len 敏感的 MM1S 细胞系相比，Len 耐药性 MM 细胞系 MMR10R 表现出更高的 SUMO E1（SAE2）表达和更高的全局 SUMO 化修饰水平。使用新型和特异性 SUMO E1 抑制剂 TAK-981 抑制 SUMO 化可显著增强 MM 细胞系对 Len 的敏感性。此外，TAK-981 和 Len 联合使用在原发性复发性 MM 患者样本中验证了增强的抗 MM 活性。IRF4 和 c-Myc 的过表达是 Len 耐药的主要机制。Len 在 Len 耐药细胞系中对 IRF4 和 c-Myc 水平的影响有限，但 TAK-981 处理降低了 Len 耐药系中的 IRF4 和 c-Myc 表达，并与 Len 联合使用时进一步降低。我们发现 SUMO 化抑制在转录和翻译后水平降低了 IRF4。SUMO 化抑制通过降低组蛋白 H3 赖氨酸 79 的甲基化来减少 DOT1L，从而抑制 IRF4 基因转录。SUMO 化抑制还通过增强降解来降低 IRF4 蛋白水平。总体而言，我们的数据表明 SUMO 化抑制通过下调 IRF4 增强了 Len 的敏感性。
