Mutations of the BCL6 proto-oncogene disrupt its negative autoregulation in diffuse large B-cell lymphoma
Mutations of the BCL6 proto-oncogene disrupt its negative autoregulation in diffuse large B-cell lymphoma
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DOI：
10.1182/blood-2002-11-3387
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发表时间：
2003-04-15
期刊：
影响因子：
20.3
通讯作者：
Dalla-Favera, R
中科院分区：
文献类型：
--
作者：
Pasqualucci, L;Migliazza, A;Dalla-Favera, R
BCL 6原癌基因编码一种转录抑制因子，其表达在大约40%的弥漫性大B细胞淋巴瘤（DLBCL）中因染色体易位而失调。BCL 6调控序列也被生殖中心（GC）B细胞和一部分W-衍生淋巴瘤中的体细胞超突变靶向。然而，这些突变的功能后果是未知的。在这里，我们报告了一个与DLBCL特异性相关的突变子集导致BCL 6转录失调。这些突变影响位于基因的第一个非编码外显子内的2个相邻BCL 6结合位点，并且它们阻止BCL 6结合其自身的启动子，从而破坏其负性自身调节回路。这些改变在大约16%的DLBCL中发现，没有涉及BCL 6位点的染色体易位，但在正常GC B细胞中没有发现。这项研究建立了BCL 6失调的新机制，并揭示了该基因在DLBCL发病机制中的更广泛参与。(C)2003年，美国血液学会。
The BCL6 proto-oncogene encodes a transcriptional repressor whose expression is deregulated by chromosomal translocations in approximately 40% of diffuse large B-cell lymphomas (DLBCLs). The BCL6 regulatory sequences are also targeted by somatic hypermutation in germinal center (GC) B cells and in a fraction of all W-derived lymphomas. However, the functional consequences of these mutations are unknown. Here we report that a subset of mutations specifically associated with DLBCL causes deregulated BCL6 transcription., These mutations affect 2 adjacent BCL6 binding sites located within the first noncoding exon of the gene, and they prevent BCL6 from binding its own promoter, thereby disrupting its negative autoregulatory circuit. These alterations were found in approximately 16% of DLBCLs devoid of chromosomal translocations involving the BCL6 locus, but they were not found in normal GC B cells. This study establishes a novel mechanism for BCL6 deregulation and reveals a broader involvement of this gene in DLBCL pathogenesis. (C) 2003 by The American Society of Hematology.