中国病理生理杂志2022，Vol.38Issue(12)：2164-2174,11.DOI:10.3969/j.issn.1000-4718.2022.12.007
BRD4抑制剂通过靶向BTK杀伤ABC-DLBCL细胞
BRD4 inhibitors kill ABC-DLBCL cells by targeting BTK
摘要
Abstract
AIM:To investigate the effect of bromodomain-containing protein 4(BRD4)inhibitors on the via-bility and apoptosis of activated B cell-like diffuse large B-cell lymphoma(ABC-DLBCL)cells and the molecular mecha-nism. METHODS:The ABC-DLBCL cells were treated with BRD4 inhibitors JQ1 and I-BET-762,and Bruton tyrosine kinase(BTK)inhibitor ibrutinib. The viability and death of the cells were determined by CCK-8 assay and PI staining,re-spectively. The mRNA levels of BTK,phospholipase Cγ(PLCγ),LYN,SYK,interleukin-6(IL-6),MYC,protein ki-nase Cβ(PKCβ),mucosa-associated lymphoid tissue lymphoma translocation protein 1(MALT1),MYC and RELA were detected by real-time PCR. The protein levels of BTK,PLCγ,MYC and RELA were determined by Western blot. Super-enhancer around BTK gene was revealed by bioinformatics analysis. RESULTS:The ABC-DLBCL cells were sensitive to BRD4/super-enhancer inhibitors such as JQ1 and I-BET-762. Both JQ1 and I-BET-762 inhibited the chronic active B-cell receptor(BCR)/nuclear factorκB(NFκB)signaling through reducing the transcription of BTK,but they had minimal ef-fect on other components in BCR/NFκB signaling. Interestingly,there was no super-enhancer around BTK gene,and the inhibitory effect of JQ1 was likely due to disruption of BRD4 binding within BTK gene. Inhibition of BRD4 had synergic ef-fect with BTK inhibitor ibrutinib. Moreover,inhibition of BRD4 induced significant cell death in ibrutinib-resistant ABC-DLBCL cells. CONCLUSION:Inhibitors of BRD4 induce ABC-DLBCL cell death via blocking BCR/NFκB signaling and has synergic effect with BTK inhibitor. Inhibition of BRD4 might be a promising strategy for treatment of ABC-DLBCL,es-pecially ibrutinib-resistant ABC-DLBCL.关键词
活化B细胞样弥漫大B细胞淋巴瘤/含布罗莫结构域蛋白4/布鲁顿酪氨酸激酶/超级增强子/BCR/NFκB信号通路Key words
Activated B cell-like diffuse large B-cell lymphoma/Bromodomain-containing protein 4/Bruton tyrosine kinase/Super-enhancers/BCR/NFκB signaling分类
医药卫生引用本文复制引用
范志伟,吴圆圆..BRD4抑制剂通过靶向BTK杀伤ABC-DLBCL细胞[J].中国病理生理杂志,2022,38(12):2164-2174,11.基金项目
Supported by the Jiangsu Provincial University Natural Science Research Project of China(No.19KJB310012) （No.19KJB310012）
