Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA.
Genes Chromosomes Cancer. 2012 Jun;51(6):525-35. doi: 10.1002/gcc.21942. Epub 2012 Feb 15.
V(D)J recombination of antigen receptor loci (IGH, IGK, IGL, TCRA, TCRB, TCRG, and TCRD) is an essential mechanism that confers enormous diversity to the mammalian immune system. However, there are now at least six examples of intrachromosomal interstitial deletions caused by aberrant V(D)J recombination between nonantigen receptor loci; five of out these six are associated with lymphoid malignancy. The SIL-SCL fusion and deletions of CDKN2A, IKZF1, Notch1, and Bcl11b are all associated with lymphoid malignancy. These interstitial deletions seem to be species specific, as the deletions seen in mice are not seen in humans; the converse is true as well. Nucleotide sequence analysis of these rearrangements reveals the hallmarks of V(D)J recombination, including site specificity near cryptic heptamer signal sequences, exonucleolytic "nibbling" at the junction site, and nontemplated "N"-region nucleotide insertion at the junction site. Two of these interstitial deletions (murine Notch1 and Bcl11b deletions) have been detected, at low frequency, in tissues from healthy mice with no evidence of malignancy, similar to the finding of chromosomal translocations in the peripheral blood or tonsils of healthy individuals. The contention that these are mediated via V(D)J recombination is strengthened by in vivo assays using extrachromosomal substrates, and chromatin immunoprecipitation-sequence analysis which shows Rag2 binding at the sites of rearrangement. Although the efficiency of these "illegitimate" recombination events is several orders of magnitude less than that at bona fide antigen receptor loci, the consequence of such deletions, namely activation of proto-oncogenes or deletion of tumor suppressor genes, is devastating, and a major cause for lymphoid malignancy.
抗原受体基因座（IGH、IGK、IGL、TCRA、TCRB、TCRG 和 TCRD）的 V(D)J 重组是赋予哺乳动物免疫系统巨大多样性的基本机制。然而，现在至少有六个例子表明，由于非抗原受体基因座之间的异常 V(D)J 重组，导致了染色体内的间质缺失；其中五个与淋巴恶性肿瘤有关。SIL-SCL 融合和 CDKN2A、IKZF1、Notch1 和 Bcl11b 的缺失都与淋巴恶性肿瘤有关。这些间质缺失似乎是种属特异性的，因为在小鼠中看到的缺失在人类中没有看到；反之亦然。这些重排的核苷酸序列分析揭示了 V(D)J 重组的特征，包括在隐蔽的七聚体信号序列附近的位点特异性、在连接位点的外切核酸酶“蚕食”以及在连接位点的非模板化“N”-区核苷酸插入。其中两个间质缺失（鼠 Notch1 和 Bcl11b 缺失）在没有恶性肿瘤证据的健康小鼠组织中以低频率检测到，类似于在健康个体的外周血或扁桃体中检测到染色体易位的发现。通过使用染色体外基质进行体内测定，以及染色质免疫沉淀-序列分析显示 Rag2 在重排位点结合，这些是通过 V(D)J 重组介导的论点得到了加强。尽管这些“非法”重组事件的效率比真正的抗原受体基因座低几个数量级，但这些缺失的后果，即原癌基因的激活或肿瘤抑制基因的缺失，是毁灭性的，是淋巴恶性肿瘤的主要原因。
