Pasqualucci L, Migliazza A, Fracchiolla N, William C, Neri A, Baldini L, Chaganti R S, Klein U, Küppers R, Rajewsky K, Dalla-Favera R
Departments of Pathology and Genetics and Development, Columbia University, New York, NY 10032, USA.
Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11816-21. doi: 10.1073/pnas.95.20.11816.
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-GC 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.
参与Ig基因抗原驱动的体细胞超突变过程的分子机制尚不清楚，但人们普遍认为该机制仅限于Ig基因座。B细胞淋巴瘤通常在BCL-6的5'调控区出现多个体细胞突变聚集，BCL-6是一种原癌基因，编码一种在生发中心（GC）B细胞中表达且GC形成所必需的POZ/锌指转录抑制因子。为了确定BCL-6突变是一种肿瘤相关现象还是反映一种生理机制，我们筛选了单个扁桃体GC B细胞中BCL-6 5'非编码区和Ig可变重链序列中的突变。30%的GC B细胞而非未成熟B细胞在BCL-6第一内含子内分析的742 bp区域出现突变（总体频率：5×10-4/bp）。相应地，在淋巴恶性肿瘤中的进一步研究表明，BCL-6突变仅限于表现出GC或GC后表型且携带突变Ig可变重链序列的B细胞肿瘤。这些结果表明，在GC B细胞中活跃的体细胞超突变机制在生理上靶向非Ig序列。
