Welzel N, Le T, Marculescu R, Mitterbauer G, Chott A, Pott C, Kneba M, Du M Q, Kusec R, Drach J, Raderer M, Mannhalter C, Lechner K, Nadel B, Jaeger U
Department of Internal Medicine, University of Vienna, Austria.
Cancer Res. 2001 Feb 15;61(4):1629-36.
The t(11;14)(q13;q32) between the BCL-1 and immunoglobulin heavy chain gene (IgH) loci in mantle cell lymphoma (MCL) are believed to be mediated by the mechanism of V(D)J recombination similar to the t(14; 18) in follicular lymphoma (FL). We have recently shown that the t(14;18) event creates staggered double-strand breaks in the BCL-2 locus, and that the t(14;18) junctions contain templated nucleotide insertions (T-nucleotides; U. Jäger et al., Blood, 95: 3520-3529, 2000). Reasoning that the earlier (pregerminal center) B-cell origin of MCL might be reflected in a different molecular structure of the chromosomal breakpoints, we PCR-amplified diagnostic samples from 93 patients. Thirty-six samples (39%) were positive for the direct (BCL-1/J(H)) and 23 for both direct and reciprocal (D(H)/BCL-1) junctions. The breaks on chromosome 14 exhibited features of V(D)J-mediated recombination as shown by D(H) and J(H) coding end processing. However, duplications of BCL-1 sequences in 39% of the 23 patients indicate staggered double-strand breaks in the major translocation cluster region (MTC). This is incompatible with V(D)J recombination and indicates a different mechanism of cleavage. The use of J(H)6 in the junctions (39%) was similar to that in the immunoglobulin genes of normal B cells and B-CLL, but considerably less than in FL. Only 2 of 36 samples contained a BCL-1/DJ(H) rearrangement, which was indicative of a previous DJ(H) rearrangement. Most importantly, 19% of the BCL-1/IgH junctions with inserts of > or =5 nucleotides contained error-prone copies (T-nucleotides) of 8-12 nucleotides originating from the surrounding BCL-1 or IgH regions, a lower rate than in FL. No correlation was found between the addition of T-nucleotides and the rate of somatic mutation in the immunoglobulin genes. We conclude that the t(11;14) and t(14;18) use the same basic mechanism of translocation including V(D)J-mediated recombination, double-strand staggered breaks, and template-dependent, error-prone DNA-synthesis. However, the distinct differences in the utilization of J(H) regions suggest that the t(11;14) occurs predominantly during an attempted primary D(H)-J(H) rearrangement in early B cells, whereas the t(14;18) mostly occurs during secondary rearrangement. This is in agreement with the pregerminal center B-cell origin of MCL.
套细胞淋巴瘤（MCL）中BCL-1与免疫球蛋白重链基因（IgH）基因座之间的t(11;14)(q13;q32)被认为是由V(D)J重组机制介导的，类似于滤泡性淋巴瘤（FL）中的t(14;18)。我们最近发现，t(14;18)事件在BCL-2基因座产生交错双链断裂，且t(14;18)连接点包含模板化核苷酸插入（T核苷酸；U. Jäger等人，《血液》，95: 3520 - 3529，2000）。鉴于MCL较早的（生发中心前）B细胞起源可能反映在染色体断点的不同分子结构中，我们对93例患者诊断样本进行了PCR扩增。36个样本（39%）直接（BCL-1/J(H)）呈阳性，23个样本直接和 reciprocal（D(H)/BCL-1）连接点均呈阳性。14号染色体上的断裂表现出V(D)J介导重组的特征，如D(H)和J(H)编码末端加工所示。然而，23例患者中有39%的BCL-1序列重复表明主要易位簇区域（MTC）存在交错双链断裂。这与V(D)J重组不相符，表明存在不同的切割机制。连接点中J(H)6的使用（39%）与正常B细胞和B - CLL的免疫球蛋白基因中的使用情况相似，但远低于FL中的使用情况。36个样本中只有2个包含BCL-1/DJ(H)重排，这表明先前存在DJ(H)重排。最重要的是，19%的BCL-1/IgH连接点插入≥5个核苷酸，其中包含8 - 12个核苷酸的易出错拷贝（T核苷酸），这些拷贝源自周围的BCL-1或IgH区域，其发生率低于FL。未发现T核苷酸的添加与免疫球蛋白基因中体细胞突变率之间存在相关性。我们得出结论，t(11;14)和t(14;18)使用相同的基本易位机制，包括V(D)J介导的重组、双链交错断裂以及模板依赖性、易出错的DNA合成。然而，J(H)区域利用的明显差异表明，t(11;14)主要发生在早期B细胞中初级D(H)-J(H)重排尝试期间，而t(14;18)大多发生在次级重排期间。这与MCL生发中心前B细胞起源一致。
