Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA.
Blood. 2012 Oct 4;120(14):2864-7. doi: 10.1182/blood-2012-02-412791. Epub 2012 Aug 20.
Previous studies have implicated activation-induced cytidine deaminase (AID) in B-cell translocations but have failed to identify any association between their chromosomal breakpoints and known AID target sequences. Analysis of 56 unclustered IgH-CCND1 translocations in mantle cell lymphoma across the ~ 344-kb bcl-1 breakpoint locus demonstrates that half of the CCND1 breaks are near CpG dinucleotides. Most of these CpG breaks are at CGC motifs, and half of the remaining breaks are near WGCW, both known AID targets. These findings provide the strongest evidence to date that AID initiates chromosomal breaks in translocations that occur in human bone marrow B-cell progenitors. We also identify WGCW breaks at the MYC locus in Burkitt lymphoma translocations and murine IgH-MYC translocations, both of which arise in mature germinal center B cells. Finally, we propose a developmental model to explain the transition from CpG breaks in early human B-cell progenitors to WGCW breaks in later stage B cells.
先前的研究表明激活诱导的胞嘧啶脱氨酶（AID）参与 B 细胞易位，但未能确定其染色体断裂点与已知的 AID 靶序列之间的任何关联。对套细胞淋巴瘤中 56 个未聚类的 IgH-CCND1 易位进行分析，跨越约 344kb 的 bcl-1 断裂点基因座，结果表明 CCND1 断裂的一半靠近 CpG 二核苷酸。这些 CpG 断裂大多位于 CGC 基序附近，其余断裂的一半靠近 WGCW，这两者都是已知的 AID 靶标。这些发现为 AID 启动人类骨髓 B 细胞前体细胞中发生的染色体断裂的假设提供了迄今为止最强有力的证据。我们还在伯基特淋巴瘤易位和小鼠 IgH-MYC 易位中鉴定出 MYC 基因座的 WGCW 断裂，这两种易位均发生在成熟生发中心 B 细胞中。最后，我们提出了一个发展模型来解释从早期人类 B 细胞前体细胞中的 CpG 断裂到晚期 B 细胞中的 WGCW 断裂的转变。
