AID assists DNMT1 to attenuate BCL6 expression through DNA methylation in diffuse large B-cell lymphoma cell lines
AID assists DNMT1 to attenuate BCL6 expression through DNA methylation in diffuse large B-cell lymphoma cell lines
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AID 通过 DNA 甲基化协助 DNMT1 在弥漫性大 B 细胞淋巴瘤细胞系中减弱 BCL6 表达
DOI：
10.1016/j.neo.2020.01.002
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发表时间：
2020-03-01
期刊：
影响因子：
4.8
通讯作者：
Ji, Yanhong
中科院分区：
文献类型：
--
作者：
Jiao, Junna;Lv, Zhuangwei;Ji, Yanhong
BCL 6原癌基因编码一个转录抑制因子，它是生发中心（GC）形成和淋巴瘤发生所必需的。已有研究报道BCL 6的组成性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）。然而，其他没有结构变体的DLBCL（45%）的特征在于通过未知机制异常高水平的BCL 6表达。在此，我们报告了AID或甲基转移酶1（DNMT 1）的缺陷触发高水平的BCL 6表达。AID-DNMT 1复合物与BCL 6启动子-0.4kb ~0kb区域结合，导致BCL 6甲基化，从而抑制BCL 6的表达。蛋白酶体途径抑制剂MG 132诱导AID和DNMT 1的积累，导致BCL 6表达降低，并导致DLBCL细胞异种移植小鼠中的细胞凋亡和肿瘤生长抑制。这些发现提出了AID在协助DNMT 1维持BCL 6甲基化中的替代辅因子作用的机制见解，从而抑制DLBCL中的BCL 6转录。这一新的机制将为DLBCL的治疗提供新的药物选择。
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.