Portis Toni, Dyck Patricia, Longnecker Richard
Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Ward 6-231, 303 East Chicago Ave, Chicago, IL 60611, USA.
Blood. 2003 Dec 1;102(12):4166-78. doi: 10.1182/blood-2003-04-1018. Epub 2003 Aug 7.
Epstein-Barr virus (EBV) is associated with the development of a variety of malignancies, including Hodgkin lymphoma. One of the few viral transcripts expressed in EBV-positive Hodgkin/Reed-Sternberg (HRS) cells of Hodgkin lymphoma is latent membrane protein 2A (LMP2A). This viral protein blocks B-cell receptor (BCR)-signaling in vitro. Furthermore, expression of LMP2A in developing B cells in vivo induces a global down-regulation of genes necessary for proper B-cell development. In this study we have analyzed gene transcription in primary B cells from LMP2A transgenic mice, LMP2A-expressing human B-cell lines, and LMP2A-positive and -negative EBV-infected lymphoblastoid cell lines (LCLs). We demonstrate that LMP2A increases the expression of genes associated with cell cycle induction and inhibition of apoptosis, alters the expression of genes involved in DNA and RNA metabolism, and decreases the expression of B-cell-specific factors and genes associated with immunity. Furthermore, many alterations in gene expression induced by LMP2A are similar to those recently described in HRS cells of Hodgkin lymphoma and activated, proliferating germinal center centroblasts/centrocytes. These correlations suggest that LMP2A expression in EBV-infected B cells may lead to the induction and maintenance of an activated, proliferative state that could ultimately result in the development of Hodgkin lymphoma.
爱泼斯坦-巴尔病毒（EBV）与多种恶性肿瘤的发生有关，包括霍奇金淋巴瘤。在霍奇金淋巴瘤的EBV阳性霍奇金/里德-斯腾伯格（HRS）细胞中表达的少数病毒转录本之一是潜伏膜蛋白2A（LMP2A）。这种病毒蛋白在体外可阻断B细胞受体（BCR）信号传导。此外，LMP2A在体内发育中的B细胞中的表达会导致正常B细胞发育所需基因的整体下调。在本研究中，我们分析了来自LMP2A转基因小鼠的原代B细胞、表达LMP2A的人B细胞系以及LMP2A阳性和阴性EBV感染的淋巴母细胞系（LCLs）中的基因转录。我们证明，LMP2A增加了与细胞周期诱导和凋亡抑制相关的基因的表达，改变了参与DNA和RNA代谢的基因的表达，并降低了B细胞特异性因子和与免疫相关的基因的表达。此外，LMP2A诱导的基因表达的许多变化与最近在霍奇金淋巴瘤的HRS细胞以及活化、增殖的生发中心中心母细胞/中心细胞中描述的变化相似。这些相关性表明，EBV感染的B细胞中LMP2A的表达可能导致激活、增殖状态的诱导和维持，最终可能导致霍奇金淋巴瘤的发生。
