抗凋亡蛋白 BCL2A1 在弥漫性大 B 细胞淋巴瘤 (DLBCL) 中高度表达，但表达非常不均匀。特别是在对当前疗法产生耐药性的情况下，BCL2A1 似乎在保护癌细胞免于诱导细胞死亡方面发挥着重要作用。降低 BCL2A1 水平可能具有治疗潜力，但目前尚无特异性抑制剂。在这项研究中，我们假设表观遗传读数器调节的信号网络可能调节 BCL2A1 的转录，因此抑制布罗莫结构域和末端外 (BET) 蛋白可能会降低 BCL2A1 表达，从而导致 DLBCL 细胞系的细胞死亡。我们发现乙酰赖氨酸竞争性 BET 抑制剂的作用机制与诱导 BET 蛋白降解的蛋白水解靶向嵌合体 (PROTAC) 的作用机制不同。两类 BETi 均降低了 BCL2A1 的表达，这与 c-MYC 的显着下调相一致。从机制上讲，BET 抑制减弱了活化 B 细胞的典型核因子 kappa 轻链增强子 (NFκB) 信号通路的组成型活性，并抑制 p65 激活。此外，通过抑制 BET 蛋白，激活转录 (STAT) 信号传导的信号转导器会减少，从而靶向 DLBCL 中通常持续活跃的另一条通路。这两条通路也被 IκB 激酶抑制剂 TPCA-1 抑制，导致 BCL2A1 和 c-MYC 表达减少。总而言之，我们的研究强调了一个新颖的复杂调控网络，该网络将 BET 蛋白与控制 DLBCL 中 BCL2A1 和 c-MYC 表达的 NFκB 和 STAT 存活信号通路联系起来。© 2024。作者。

The antiapoptotic protein BCL2A1 is highly, but very heterogeneously expressed in Diffuse Large B-cell Lymphoma (DLBCL). Particularly in the context of resistance to current therapies, BCL2A1 appears to play an important role in protecting cancer cells from the induction of cell death. Reducing BCL2A1 levels may have therapeutic potential, however, no specific inhibitor is currently available. In this study, we hypothesized that the signaling network regulated by epigenetic readers may regulate the transcription of BCL2A1 and hence that inhibition of Bromodomain and Extra-Terminal (BET) proteins may reduce BCL2A1 expression thus leading to cell death in DLBCL cell lines. We found that the mechanisms of action of acetyl-lysine competitive BET inhibitors are different from those of proteolysis targeting chimeras (PROTACs) that induce the degradation of BET proteins. Both classes of BETi reduced the expression of BCL2A1 which coincided with a marked downregulation of c-MYC. Mechanistically, BET inhibition attenuated the constitutively active canonical nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB) signaling pathway and inhibited p65 activation. Furthermore, signal transducer of activated transcription (STAT) signaling was reduced by inhibiting BET proteins, targeting another pathway that is often constitutively active in DLBCL. Both pathways were also inhibited by the IκB kinase inhibitor TPCA-1, resulting in decreased BCL2A1 and c-MYC expression. Taken together, our study highlights a novel complex regulatory network that links BET proteins to both NFκB and STAT survival signaling pathways controlling both BCL2A1 and c-MYC expression in DLBCL.© 2024. The Author(s).