BCL-6 mutations in normal germinal center B cells:: Evidence of somatic hypermutation acting outside Ig loci
BCL-6 mutations in normal germinal center B cells:: Evidence of somatic hypermutation acting outside Ig loci
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DOI：
10.1073/pnas.95.20.11816
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发表时间：
1998-09-29
影响因子：
11.1
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
Ig基因在抗原驱动的体细胞超突变过程中所涉及的分子机制尚不清楚，但普遍认为这一机制仅限于Ig基因座。B细胞淋巴瘤通常表现为多个体细胞突变，聚集在bcl6的5‘-调控区，bcl6是一种原癌基因，编码POZ/锌指转录抑制因子，在生发中心(GC)B细胞中表达，是GC形成所必需的。为了确定bcl6突变是否代表一种肿瘤相关现象或反映一种生理机制，我们筛选了单个人扁桃体GC B细胞，以检测发生在bcl6 5‘非编码区和Ig可变重链序列中的突变。30%的GC B细胞，而不是幼稚的B细胞，在BCL-6的第一内含子分析的742个碱基区域有突变(总频率：5×10(-4)/个碱基)。相应地，在淋巴系统恶性肿瘤中的一项扩展调查表明，bcl6突变仅限于表现为GC或CC后表型的B细胞肿瘤，并携带突变的Ig可变重链序列。这些结果表明，GC B细胞中活跃的体细胞超突变机制在生理上针对非Ig序列。
The molecular mechanism involved in the process of antigen-driven somatic hypermutation of Ig genes is unknown, but it is commonly believed that this mechanism is restricted to the Ig loci. B cell lymphomas commonly display multiple somatic mutations clustering in the 5'-regulatory region of BCL-6, a proto-oncogene encoding for a POZ/Zinc finger transcriptional repressor expressed in germinal center (GC) B cells and required for GC formation. To determine whether BCL-6 mutations represent a tumor-associated phenomenon or reflect a physiologic mechanism, we screened single human tonsillar GC B cells for mutations occurring in the BCL-6 5'-noncoding region and in the Ig variable heavy chain sequences. Thirty percent of GC B cells, but not naive B cells, displayed mutations in the 742 bp region analyzed within the first intron of BCL-6 (overall frequency: 5 x 10(-4)/bp). Accordingly, an expanded survey in lymphoid malignancies showed that BCL-6 mutations are restricted to B cell tumors displaying GC or post-CC phenotype and carrying mutated Ig variable heavy chain sequences, These results indicate that the somatic hypermutation mechanism active in GC B cells physiologically targets non-Ig sequences.