The BCL6 proto-oncogene encodes a transcriptional repressor, which is required for germinal centers (GCs) formation and lymphomagenesis. Previous studies have been reported that the constitutive expression of BCL6 leads to diffuse large B cell lymphoma (DLBCL) through activation-induced cytidine deaminase (AID) mediated chromosomal translocations and mutations. However, other DLBCLs (45%) without structural variants were characterized by abnormally high level of BCL6 expression through an unknown mechanism. Herein, we report that deficiency in AID or methyltransferase 1 (DNMT1) triggers high level of BCL6 expression. AID-DNMT1 complex binds to -0.4 kb -0 kb region of BCL6 promoter and contributes to generate BCL6 methylation which results in inhibition of BCL6 expression. The proteasome pathway inhibitor MG132 induces accumulation of AID and DNMT1, causes decreased BCL6 expression, and leads to cell apoptosis and tumor growth inhibition in DLBCL cell xenograft mice. These findings propose mechanistic insight into an alternative cofactor role of AID in assisting DNMT1 to maintain BCL6 methylation, thus suppress BCL6 transcription in DLBCL. This novel mechanism will provide a new drug selection in the therapeutic approach to DLBCL in the future.

中文翻译：

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AID通过弥漫性大B细胞淋巴瘤细胞系中的DNA甲基化来协助DNMT1减弱BCL6表达。

BCL6原癌基因编码一个转录阻遏物，这是生发中心（GCs）形成和淋巴瘤发生所必需的。先前的研究报道了BCL6的组成型表达通过激活诱导的胞苷脱氨酶（AID）介导的染色体易位和突变导致弥漫性大B细胞淋巴瘤（DLBCL）。但是，其他无结构变异的DLBCL（45％）的特征是通过未知机制异常高水平的BCL6表达。在此，我们报道AID或甲基转移酶1（DNMT1）的缺乏会触发BCL6表达的高水平。AID-DNMT1复合物与BCL6启动子的-0.4 kb -0 kb区域结合，并有助于产生BCL6甲基化，从而抑制BCL6表达。蛋白酶体途径抑制剂MG132诱导AID和DNMT1积累，导致BCL6表达下降，并导致DLBCL细胞异种移植小鼠的细胞凋亡和肿瘤生长抑制。这些发现提出了对AID在协助DNMT1维持BCL6甲基化，从而抑制BCL6在DLBCL中转录中的辅助因子的替代作用的机制的认识。这种新颖的机制将为将来的DLBCL治疗方法提供新的药物选择。