School of Cancer Sciences, University of Birmingham, B15 2TT, UK.
The Cancer Epigenetics Laboratory, Sir YK Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, 999077, Hong Kong.
Pathogens. 2012 Oct 8;1(2):83-101. doi: 10.3390/pathogens1020083.
B-lymphocyte-induced maturation protein 1 (BLIMP1) exists as two major isoforms, α and β, which arise from alternate promoters. Inactivation of the full length BLIMP1α isoform is thought to contribute to B cell lymphomagenesis by blocking post-germinal centre (GC) B cell differentiation. In contrast, the shorter β isoform is functionally impaired and over-expressed in several haematological malignancies, including diffuse large B cell lymphomas (DLBCL). We have studied the influence on BLIMP1β expression of the Epstein-Barr virus (EBV), a human herpesvirus that is implicated in the pathogenesis of several GC-derived lymphomas, including a subset of DLBCL and Hodgkin's lymphoma (HL). We show that BLIMP1β expression is increased following the EBV infection of normal human tonsillar GC B cells. We also show that this change in expression is accompanied by hypomethylation of the BLIMP1β-specific promoter. Furthermore, we confirmed previous reports that the BLIMP1β promoter is hypomethylated in DLBCL cell lines and show for the first time that BLIMP1β is hypomethylated in the Hodgkin/Reed-Sternberg (HRS) cells of HL. Our results provide evidence in support of a role for BLIMP1β in the pathogenesis of EBV-associated B cell lymphomas.
B 淋巴细胞诱导成熟蛋白 1（BLIMP1）有两种主要的异构体，α 和 β，它们由不同的启动子产生。全长 BLIMP1α 异构体的失活被认为通过阻断生发中心（GC）后 B 细胞分化而促进 B 细胞淋巴瘤的发生。相比之下，较短的β 异构体功能受损，并在几种血液恶性肿瘤中过度表达，包括弥漫性大 B 细胞淋巴瘤（DLBCL）。我们研究了 Epstein-Barr 病毒（EBV）对 BLIMP1β 表达的影响，EBV 是一种人类疱疹病毒，与几种 GC 衍生的淋巴瘤，包括一部分 DLBCL 和霍奇金淋巴瘤（HL）的发病机制有关。我们表明，EBV 感染正常人扁桃体 GC B 细胞后，BLIMP1β 的表达增加。我们还表明，这种表达变化伴随着 BLIMP1β 特异性启动子的低甲基化。此外，我们证实了先前关于 DLBCL 细胞系中 BLIMP1β 启动子低甲基化的报告，并首次表明 BLIMP1β 在 HL 的霍奇金/里德-斯特恩伯格（HRS）细胞中低甲基化。我们的结果为 BLIMP1β 在 EBV 相关 B 细胞淋巴瘤的发病机制中发挥作用提供了证据。
