Pasqualucci Laura, Compagno Mara, Houldsworth Jane, Monti Stefano, Grunn Adina, Nandula Subhadra V, Aster Jon C, Murty Vundavally V, Shipp Margaret A, Dalla-Favera Riccardo
Institute for Cancer Genetics and 2The Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
J Exp Med. 2006 Feb 20;203(2):311-7. doi: 10.1084/jem.20052204.
PR domain containing 1 with zinc finger domain (PRDM1)/B lymphocyte-induced maturation protein 1 (BLIMP1) is a transcriptional repressor expressed in a subset of germinal center (GC) B cells and in all plasma cells, and required for terminal B cell differentiation. The BLIMP1 locus lies on chromosome 6q21-q22.1, a region frequently deleted in B cell lymphomas, suggesting that it may harbor a tumor suppressor gene. We report here that the BLIMP1 gene is inactivated by structural alterations in 24% (8 out of 34) activated B cell-like diffuse large cell lymphoma (ABC-DLBCL), but not in GC B cell-like (n = 0/37) or unclassified (n = 0/21) DLBCL. BLIMP1 alterations included gene truncations, nonsense mutations, frameshift deletions, and splice site mutations that generate aberrant transcripts encoding truncated BLIMP1 proteins. In all cases studied, both BLIMP1 alleles were inactivated by deletions or mutations. Furthermore, most non-GC type DLBCL cases (n = 20/26, 77%) lack BLIMP1 protein expression, despite the presence of BLIMP1 mRNA. These results indicate that a sizable fraction of ABC-DLBCL carry an inactive BLIMP1 gene, and suggest that the same gene is inactivated by epigenetic mechanisms in an additional large number of cases. These findings point to a role for BLIMP1 as a tumor suppressor gene, whose inactivation may contribute to lymphomagenesis by blocking post-GC differentiation of B cells toward plasma cells.
含锌指结构域的PR结构域蛋白1（PRDM1）/B淋巴细胞诱导成熟蛋白1（BLIMP1）是一种转录抑制因子，在生发中心（GC）B细胞亚群和所有浆细胞中表达，是B细胞终末分化所必需的。BLIMP1基因座位于6号染色体q21 - q22.1区域，该区域在B细胞淋巴瘤中经常缺失，提示其中可能含有一个肿瘤抑制基因。我们在此报告，在24%（34例中有8例）的活化B细胞样弥漫大B细胞淋巴瘤（ABC - DLBCL）中，BLIMP1基因因结构改变而失活，但在GC B细胞样（n = 0/37）或未分类（n = 0/21）的DLBCL中未发现这种情况。BLIMP1的改变包括基因截短、无义突变、移码缺失和剪接位点突变，这些突变产生编码截短BLIMP1蛋白的异常转录本。在所有研究的病例中，两个BLIMP1等位基因均因缺失或突变而失活。此外，尽管存在BLIMP1 mRNA，但大多数非GC型DLBCL病例（n = 20/26，77%）缺乏BLIMP1蛋白表达。这些结果表明，相当一部分ABC - DLBCL携带失活的BLIMP1基因，并提示在另外大量病例中，同一基因通过表观遗传机制失活。这些发现表明BLIMP1作为一个肿瘤抑制基因发挥作用，其失活可能通过阻断B细胞在GC期后向浆细胞的分化而促进淋巴瘤发生。
