Role of Epstein–Barr Virus C Promoter Deletion in Diffuse Large B Cell Lymphoma
爱泼斯坦-巴尔病毒 C 启动子缺失在弥漫性大 B 细胞淋巴瘤中的作用
The C promoter of Epstein–Barr virus is assumed to be important for B cell growth and transformation. However, we present evidence that promoter activity is not only unneeded for transformation but also that absence of the promoter increased the transformation activity of the virus. We found that the C promoter was lost in some Epstein–Barr virus-associated lymphoma specimens. Therefore, deletion of the promoter could partially account for the tumorigenesis of Epstein–Barr virus-associated lymphomas.
Epstein-Barr 病毒的 C 启动子被认为对 B 细胞的生长和转化很重要。然而，我们提供的证据表明，启动子活性不仅不需要转化，而且启动子的缺失也增加了病毒的转化活性。我们发现 C 启动子在一些 Epstein-Barr 病毒相关淋巴瘤标本中丢失。因此，启动子的缺失可以部分解释 Epstein-Barr 病毒相关淋巴瘤的肿瘤发生。
The Epstein–Barr virus (EBV) is the cause of several malignancies, including diffuse large B cell lymphoma (DLBCL). We recently found that EBV genomes in EBV-positive cancer specimens have various deletions (Okuno et al. Nat Microbiol. 2019). Here, we focus on the deletion of C promoter (Cp), which transcribes EBV nuclear antigen (EBNA) genes in type III latency. The Cp deletion found in a DLBCL patient (332 bp) was introduced into EBV-BAC of the B95-8 strain. Interestingly, the dCp virus transformed B cells more efficiently than WT and revertant strains. Deletion of Cp also promoted tumor formation and severe pathogenicity in a mouse xenograft model. RNA sequencing and qRT–PCR analyses revealed that Cp transcription was undetectable in the dCp cells. Instead, transcription from the W promoter (Wp), an alternative promoter for EBNA, was activated in the dCp mutant. We also found that the expression of latent membrane protein 2A (LMP2A) was somehow induced in the dCp mutant. Double knockout of Cp and LMP2A indicated that LMP2A is crucial for B cell transformation, but the increased transformation induced by Cp deletion cannot be explained by LMP2A alone. We also tested the effect of an anti-apoptotic viral BCL2 homolog, BHRF1, because its expression was reportedly induced more efficiently by that of Wp. However, increased growth transformation via Cp deletion was not due to the BHRF1 gene. Taken together, the results indicated that deletion of a specific region in Cp increased in vitro transformation and the rate of progression of EBV-positive lymphoproliferative disorders in vivo. Our data suggest that genomic alteration not only of the host but also the virus promotes EBV-positive tumor generation and expansion, although the molecular mechanism underlying this phenomenon is still unclear. However, LMP2A and BHRF1 are not involved.
爱泼斯坦-巴尔病毒 (EBV) 是多种恶性肿瘤的病因，包括弥漫性大 B 细胞淋巴瘤 (DLBCL)。我们最近发现 EBV 阳性癌症标本中的 EBV 基因组具有各种缺失（Okuno 等人 Nat Microbiol. 2019）。在这里，我们专注于 C 启动子 (Cp) 的缺失，它在 III 型潜伏期中转录 EBV 核抗原 (EBNA) 基因。在 DLBCL 患者 (332 bp) 中发现的 Cp 缺失被引入 B95-8 菌株的 EBV-BAC。有趣的是，dCp 病毒比 WT 和回复毒株更有效地转化 B 细胞。Cp 的删除也促进了小鼠异种移植模型中的肿瘤形成和严重的致病性。RNA 测序和 qRT-PCR 分析显示，在 dCp 细胞中检测不到 Cp 转录。相反，从 W 启动子 (Wp) 的转录，EBNA 的替代启动子，在 dCp 突变体中被激活。我们还发现潜伏膜蛋白 2A (LMP2A) 的表达在 dCp 突变体中以某种方式被诱导。Cp和LMP2A的双重敲除表明LMP2A对B细胞转化至关重要，但Cp缺失诱导的转化增加不能单独用LMP2A解释。我们还测试了抗凋亡病毒 BCL2 同源物 BHRF1 的作用，因为据报道它的表达被 Wp 更有效地诱导。然而，通过 Cp 缺失增加的生长转化不是由于 BHRF1 基因。总之，结果表明，删除 Cp 中的特定区域会增加体外转化和体内 EBV 阳性淋巴增殖性疾病的进展速度。我们的数据表明，不仅宿主的基因组改变，而且病毒的基因组改变都促进了 EBV 阳性肿瘤的产生和扩张，尽管这种现象背后的分子机制仍不清楚。但是，不涉及 LMP2A 和 BHRF1。
Deletion of the Cp, originally found in EBV-positive DLBCL, appeared to increase growth transformation efficiency. Although the molecular mechanism of this phenomenon is still elusive, loss of part of the EBV gene may increase tumorigenicity.
最初在 EBV 阳性 DLBCL 中发现的 Cp 缺失似乎增加了生长转化效率。虽然这种现象的分子机制仍然难以捉摸，但部分 EBV 基因的缺失可能会增加致瘤性。
关键词： EBV,DLBCL ,C启动子,LMP2A ,BHRF1,成长转型EBV,DLBCL,C promoter, LMP2A, BHRF1, growth transformation
来源： MDPI https://www.mdpi.com/2072-6694/13/3/561/htm