Iqbal J, Greiner T C, Patel K, Dave B J, Smith L, Ji J, Wright G, Sanger W G, Pickering D L, Jain S, Horsman D E, Shen Y, Fu K, Weisenburger D D, Hans C P, Campo E, Gascoyne R D, Rosenwald A, Jaffe E S, Delabie J, Rimsza L, Ott G, Müller-Hermelink H K, Connors J M, Vose J M, McKeithan T, Staudt L M, Chan W C
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Leukemia. 2007 Nov;21(11):2332-43. doi: 10.1038/sj.leu.2404856. Epub 2007 Jul 12.
Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed biologically and prognostically distinct subgroups: germinal center B-cell-like (GCB), activated B-cell-like (ABC) and primary mediastinal (PM) DLBCL. The BCL6 gene is often translocated and/or mutated in DLBCL. Therefore, we examined the BCL6 molecular alterations in these DLBCL subgroups, and their impact on BCL6 expression and BCL6 target gene repression. BCL6 translocations at the major breakpoint region (MBR) were detected in 25 (18.8%) of 133 DLBCL cases, with a higher frequency in the PM (33%) and ABC (24%) subgroups than in the GCB (10%) subgroup. Translocations at the alternative breakpoint region (ABR) were detected in five (6.4%) of 78 DLBCL cases, with three cases in ABC and one case each in the GCB and the unclassifiable subgroups. The translocated cases involved IgH and non-IgH partners in about equal frequency and were not associated with different levels of BCL6 mRNA and protein expression. BCL6 mutations were detected in 61% of DLBCL cases, with a significantly higher frequency in the GCB and PM subgroups (>70%) than in the ABC subgroup (44%). Exon-1 mutations were mostly observed in the GCB subgroup. The repression of known BCL6 target genes correlated with the level of BCL6 mRNA and protein expression in GCB and ABC subgroups but not with BCL6 translocation and intronic mutations. No clear inverse correlation between BCL6 expression and p53 expression was observed. Patients with higher BCL6 mRNA or protein expression had a significantly better overall survival. The biological role of BCL6 in translocated cases where repression of known target genes is not demonstrated is intriguing and warrants further investigation.
弥漫性大B细胞淋巴瘤（DLBCL）的基因表达谱分析揭示了生物学特性和预后不同的亚组：生发中心B细胞样（GCB）、活化B细胞样（ABC）和原发性纵隔（PM）DLBCL。BCL6基因在DLBCL中常发生易位和/或突变。因此，我们研究了这些DLBCL亚组中的BCL6分子改变及其对BCL6表达和BCL6靶基因抑制的影响。在133例DLBCL病例中的25例（18.8%）检测到主要断裂点区域（MBR）的BCL6易位，在PM（33%）和ABC（24%）亚组中的频率高于GCB（10%）亚组。在78例DLBCL病例中的5例（6.4%）检测到替代断裂点区域（ABR）的易位，其中3例在ABC亚组，GCB亚组和无法分类亚组各1例。易位病例涉及IgH和非IgH伙伴的频率大致相等，且与不同水平的BCL6 mRNA和蛋白表达无关。在61%的DLBCL病例中检测到BCL6突变，在GCB和PM亚组中的频率显著高于ABC亚组（>70%对44%）。外显子1突变大多在GCB亚组中观察到。已知BCL6靶基因的抑制与GCB和ABC亚组中BCL6 mRNA和蛋白表达水平相关，但与BCL6易位和内含子突变无关。未观察到BCL6表达与p53表达之间明显的负相关。BCL6 mRNA或蛋白表达较高的患者总生存期明显更好。在未证明已知靶基因受到抑制的易位病例中，BCL6的生物学作用很有趣，值得进一步研究。
