6月12日，Cancer Cell雜志報(bào)道了彌散性大B細(xì)胞淋巴瘤化學(xué)協(xié)同治療的最新進(jìn)展,。
癌基因突變的知識(shí),，可催生靶向性殺死癌細(xì)胞而避免正常細(xì)胞受害的治療手段。來(lái)那度胺在彌散性大B細(xì)胞淋巴瘤（DLBCL）的活化B細(xì)胞樣（ABC）亞型中是一種活性藥物,。由于ABC DLBCL細(xì)胞中存在MYD88癌基因,，來(lái)那度胺可通過(guò)促進(jìn)干擾素β (IFNβ)的產(chǎn)生來(lái)殺死這些癌細(xì)胞。
來(lái)那度胺以cereblon依賴的方式下調(diào)IRF4和SPIB的水平,。這兩個(gè)轉(zhuǎn)錄因子一起通過(guò)抑制IRF7和上調(diào)促生存的NF-kappa-B信號(hào)通路預(yù)防IFNβ的產(chǎn)生,。利用Bruton 的酚基乙氨酸激酶(BTK) 抑制劑ibrutinib阻斷B細(xì)胞受體信號(hào)，也可下調(diào)IRF4,，并與來(lái)那度胺協(xié)同殺傷ABC DLBCL細(xì)胞,。該研究表明，ibrutinib與來(lái)那度胺結(jié)合或可成為新的治療策略,。（生物谷bioon.com）
doi:10.1016/j.cell.2011.10.017
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Exploiting Synthetic Lethality for the Therapy of ABC Diffuse Large B Cell Lymphoma
Yibin Yang, Arthur L. Shaffer, N.C. Tolga Emre, Michele Ceribelli, Meili Zhang, George Wright, Wenming Xiao, John Powell
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-B 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.
