Structural alterations of the BCL-6 gene in B cell lymphoma
Structural alterations of the BCL-6 gene in B cell lymphoma
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B 细胞淋巴瘤中 BCL-6 基因的结构改变
DOI：
10.1016/0165-4608(95)90006-3
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发表时间：
1995
期刊：
影响因子：
--
通讯作者：
K. Offit
中科院分区：
文献类型：
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作者：
R. Dalla;B. Ye;A. Migliazza;S. Chaganti;W. Chang;Chih;Jiandong Zhang;G. Cattoretti;H. Niu;K. Offit
弥漫性大细胞淋巴瘤（DLCL）（最常见和临床相关类型的非霍奇金淋巴瘤（NHL））的大部分（30-40%）与BCL-6基因的重排相关（Ye，BH et al.，Science 262：747，1993; Lo Coco，F等人，Blood 83：1757，1994）。这些病变具有临床意义，因为它们鉴定了以结节起源和良好预后为特征的DLCL的子集（Offit，K等人，New Engl. J. Med. 331，74，1994. BCL-6基因编码一个95 kD的核磷蛋白，优先在成熟B细胞中表达，并在浆细胞分化过程中下调。该蛋白含有6个C-末端C2 H2型锌指和一个N-末端ZIN/POZ结构域，ZIN/POZ结构域是一个推定的蛋白质-蛋白质相互作用结构域，为包括几种果蝇发育调节因子在内的锌指蛋白亚类所共有。BCL-6通过其锌指与特定的DNA序列结合，并含有一个有效的转录抑制结构域，这表明它可能作为一个转录因子发挥作用。作为影响带3q 27的重排的结果，BCL-6启动子区被截短，并且编码结构域下游连接到从其他染色体易位的异源启动子。除了染色体重排，最近的一项研究显示，在18例携带未重排BCL-6基因的DLCL病例中，有14例（78%）在跨越BCL-6第一个非编码外显子的4 kb区域内存在体细胞突变，但在190例其他活检（包括大多数类型的实体瘤）中没有。因此，考虑到重排和突变，> 80%的DLCL在BCL-6的5 '非编码区中携带改变。这些改变的频率、聚集性和疾病相关性表明它们可能通过改变BCL-6基因表达而促进淋巴瘤的发生。
A substantial fraction (30-40%) of diffuse large-cell lymphoma (DLCL), the most frequent and clinically relevant type of non-Hodgkin lymphoma (NHL), is associated with rearrangements of the BCL-6 gene (Ye, BH et al., Science 262: 747, 1993; Lo Coco, F et al., Blood 83: 1757, 1994). These lesions have clinical significance since they identify a subset of DLCL characterized by extranodal origin and favorable prognosis (Offit, K et al., New Engl. J. Med. 331, 74, 1994. The BCL-6 gene encodes a 95 kD nuclear phosphoprotein preferentially expressed in mature B-cells and down-regulated during plasmacell differentiation. This protein contains six C-terminal C 2 H 2-type zinc-fingers and a N-terminal ZIN/POZ domain, a putative protein-protein interaction domain common to a subset of zinc-finger proteins including several Drosophila developmental regulators. BCL-6 binds to specific DNA sequences through its zinc fingers and contains a potent transcriptional repressor domain suggesting that it may function as a transcription factor. As a consequence of rearrangements affecting band 3q27, the BCL-6 promoter region is truncated and the coding domain is linked downstream to heterologous promoters translocated from other chromosomes. In addition to chromosomal rearrangements, a recent study revealed the presence of somatic mutations within a 4 kb region spanning the BCL-6 first non-coding exon in 14 of 18 DLCL cases (78%) carrying unrearranged BCL-6 genes, but not in 190 other biopsies including most types of solid tumors. Thus, considering both rearrangements and mutations,> 80% of DLCL carry alterations in the 5'non coding region of BCL-6. The frequency, clustering, and disease-association of these alterations suggest that they may contribute to lymphomagenesis, presumably by altering BCL-6 gene expression.