Ye B H, Chaganti S, Chang C C, Niu H, Corradini P, Chaganti R S, Dalla-Favera R
Department of Pathology, Columbia University, New York, NY 10032, USA.
EMBO J. 1995 Dec 15;14(24):6209-17. doi: 10.1002/j.1460-2075.1995.tb00311.x.
The BCL6 gene codes for a zinc-finger transcription factor and is involved in chromosomal rearrangements in 30-40% of diffuse large-cell lymphoma (DLCL). These rearrangements cluster within the 5' regulatory region of BCL6 spanning its first non-coding exon. To determine the functional consequences of these alterations, we have analyzed the structure of the rearranged BCL6 alleles and their corresponding RNA and protein species in two DLCL biopsies and one tumor cell line which carried the t(3;14)(q27;q32) translocation involving the BCL6 and immunoglobulin heavy-chain (IgH) loci. In all three cases, the breakpoints were mapped within the IgH switch region and the BCL6 first intron, leading to the juxtaposition of part of the IgH locus upstream and in the same transcriptional orientation to the BCL6 coding exons. An analysis of cDNA clones showed that these recombinations generate chimeric IgH-BCL6 transcripts which initiated from IgH germline transcript promoters (I mu or I gamma 3), but retain a normal BCL6 coding domain. In the tumor cell line, the chimeric I gamma 3-BCL6 allele, but not the germline BCL6 gene, was transcriptionally active and produced a normal BCL6 protein. These findings indicate that t(3;14) translocations alter BCL6 expression by promoter substitution and imply that the consequence of these alterations is the deregulated expression of a normal BCL6 protein.
BCL6基因编码一种锌指转录因子，在30%-40%的弥漫性大细胞淋巴瘤（DLCL）中参与染色体重排。这些重排集中在BCL6的5'调控区域内，该区域跨越其第一个非编码外显子。为了确定这些改变的功能后果，我们分析了两个DLCL活检样本和一个肿瘤细胞系中重排的BCL6等位基因及其相应的RNA和蛋白质种类，该肿瘤细胞系携带涉及BCL6和免疫球蛋白重链（IgH）基因座的t(3;14)(q27;q32)易位。在所有三个病例中，断点均定位在IgH转换区和BCL6的第一个内含子内，导致IgH基因座的一部分在上游并列，并以相同的转录方向与BCL6编码外显子相邻。对cDNA克隆的分析表明，这些重组产生嵌合的IgH-BCL6转录本，其从IgH种系转录本启动子（Iμ或Iγ3）起始，但保留正常的BCL6编码结构域。在肿瘤细胞系中，嵌合的Iγ3-BCL6等位基因而非种系BCL6基因具有转录活性，并产生正常的BCL6蛋白。这些发现表明，t(3;14)易位通过启动子替代改变BCL6表达，并暗示这些改变的后果是正常BCL6蛋白的表达失调。
