利用合成致死性治疗 ABC 弥漫性大 B 细胞淋巴瘤。

Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma.

机构信息

Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

出版信息

Cancer Cell. 2012 Jun 12;21(6):723-37. doi: 10.1016/j.ccr.2012.05.024.

Knowledge of oncogenic mutations can inspire therapeutic strategies that are synthetically lethal, affecting cancer cells while sparing normal cells. Lenalidomide is an active agent in the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), but its mechanism of action is unknown. Lenalidomide kills ABC DLBCL cells by augmenting interferon β (IFNβ) production, owing to the oncogenic MYD88 mutations in these lymphomas. In a cereblon-dependent fashion, lenalidomide downregulates IRF4 and SPIB, transcription factors that together prevent IFNβ production by repressing IRF7 and amplify prosurvival NF-κB signaling by transactivating CARD11. Blockade of B cell receptor signaling using the BTK inhibitor ibrutinib also downregulates IRF4 and consequently synergizes with lenalidomide in killing ABC DLBCLs, suggesting attractive therapeutic strategies.

致癌基因突变的知识可以启发合成致死的治疗策略，这些策略会影响癌细胞，同时又不影响正常细胞。来那度胺是激活 B 细胞样（ABC）弥漫性大 B 细胞淋巴瘤（DLBCL）亚型的有效药物，但它的作用机制尚不清楚。由于这些淋巴瘤中的致癌 MYD88 突变，来那度胺通过增强干扰素β（IFNβ）的产生来杀死 ABC DLBCL 细胞。来那度胺以 cereblon 依赖性方式下调转录因子 IRF4 和 SPIB，这两种转录因子通过抑制 IRF7 共同阻止 IFNβ的产生，并通过转激活 CARD11 来放大 prosurvival NF-κB 信号。使用 BTK 抑制剂伊布替尼阻断 B 细胞受体信号也会下调 IRF4，因此与来那度胺协同作用，杀死 ABC DLBCL，提示有吸引力的治疗策略。