Chromosomal translocations cause deregulated BCL6 expression by promoter substitution in B cell lymphoma
Chromosomal translocations cause deregulated BCL6 expression by promoter substitution in B cell lymphoma
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DOI：
10.1002/j.1460-2075.1995.tb00311.x
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发表时间：
1995-12-15
期刊：
影响因子：
11.4
通讯作者：
DallaFavera, R
中科院分区：
文献类型：
--
作者：
Ye, BH;Chaganti, S;DallaFavera, R
BCL6基因编码一种锌指转录因子，并且在30 - 40%的弥漫性大细胞淋巴瘤（DLCL）中参与染色体重排。这些重排聚集在BCL6的5'调控区域内，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活检样本以及一个携带涉及BCL6和免疫球蛋白重链（IgH）基因座的t(3;14)(q27;q32)易位的肿瘤细胞系中重排的BCL6等位基因的结构以及它们相应的RNA和蛋白质种类。在所有三个病例中，断点都定位在IgH转换区域和BCL6第一内含子内，导致IgH基因座的一部分在上游并以与BCL6编码外显子相同的转录方向并置。对cDNA克隆的分析表明，这些重组产生了嵌合的IgH - BCL6转录本，其从IgH种系转录启动子（I - μ或I(γ)3）起始，但保留了正常的BCL6编码结构域。在肿瘤细胞系中，嵌合的I(γ)3 - BCL6等位基因（而非种系BCL6基因）具有转录活性，并产生一种正常的BCL6蛋白。这些发现表明t(3;14)易位通过启动子替换改变了BCL6的表达，并意味着这些改变的结果是一种正常BCL6蛋白的表达失调。
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.