Brien G, Trescol-Biemont M-C, Bonnefoy-Bérard N
Inserm, U503, Lyon, F-69007, France.
Oncogene. 2007 Aug 23;26(39):5828-32. doi: 10.1038/sj.onc.1210363. Epub 2007 Mar 12.
Elevated expression of the antiapoptotic protein Bfl-1 (A1) was previously reported in several cancer cell lines. Recently, molecular profiling of large B-cell lymphoma identified Bfl-1 as a gene signature in 'OxPhos' diffuse large B-cell lymphoma subtype and in primary mediastinal large B-cell lymphoma, suggesting that in addition to Bcl-2, Bcl-xL and Mcl-1, Bfl-1 may be a relevant target in the design of new strategies for cancer therapy. Using short hairpin RNA strategy, we show here that Bfl-1 silencing in one lymphoblastoid B-cell line and in two diffuse large B-cell lymphoma cell lines potently induces their apoptosis and sensitizes those cell lines to anti-CD20 (Rituximab)-mediated cell death as well as to apoptosis induced by chemotherapeutic molecules such as doxorubicin, vincristine, cisplatin and fludarabine. These results demonstrate for the first time that Bfl-1 is an essential protein for survival of malignant B cells and suggest Bfl-1 may represent a potential target for future drug development against B cell lymphoma.
先前有报道称，抗凋亡蛋白Bfl-1（A1）在多种癌细胞系中表达上调。最近，对大B细胞淋巴瘤的分子谱分析表明，Bfl-1是“氧化磷酸化”弥漫性大B细胞淋巴瘤亚型和原发性纵隔大B细胞淋巴瘤中的一种基因特征，这表明除了Bcl-2、Bcl-xL和Mcl-1之外，Bfl-1可能是癌症治疗新策略设计中的一个相关靶点。利用短发夹RNA策略，我们在此表明，在一个淋巴母细胞性B细胞系和两个弥漫性大B细胞淋巴瘤细胞系中沉默Bfl-1可有效诱导其凋亡，并使这些细胞系对抗CD20（利妥昔单抗）介导的细胞死亡以及阿霉素、长春新碱、顺铂和氟达拉滨等化疗分子诱导的凋亡敏感。这些结果首次证明Bfl-1是恶性B细胞存活所必需的蛋白质，并表明Bfl-1可能是未来抗B细胞淋巴瘤药物开发的潜在靶点。
