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Role of Epstein–Barr Virus C Promoter Deletion in Diffuse Large B Cell Lymphoma

愛潑斯坦-巴爾病毒 C 啟動(dòng)子缺失在彌漫性大 B 細(xì)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 啟動(dòng)子被認(rèn)為對(duì) B 細(xì)胞的生長(zhǎng)和轉(zhuǎn)化很重要。然而，我們提供的證據(jù)表明，啟動(dòng)子活性不僅不需要轉(zhuǎn)化，而且啟動(dòng)子的缺失也增加了病毒的轉(zhuǎn)化活性。我們發(fā)現(xiàn) C 啟動(dòng)子在一些 Epstein-Barr 病毒相關(guān)淋巴瘤標(biāo)本中丟失。因此，啟動(dòng)子的缺失可以部分解釋 Epstein-Barr 病毒相關(guān)淋巴瘤的腫瘤發(fā)生。

三角細(xì)胞搖瓶

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.

高效搖瓶

愛潑斯坦-巴爾病毒 (EBV) 是多種惡性腫瘤的病因，包括彌漫性大 B 細(xì)胞淋巴瘤 (DLBCL)。我們最近發(fā)現(xiàn) EBV 陽性癌癥標(biāo)本中的 EBV 基因組具有各種缺失（Okuno 等人 Nat Microbiol. 2019）。在這里，我們專注于 C 啟動(dòng)子 (Cp) 的缺失，它在 III 型潛伏期中轉(zhuǎn)錄 EBV 核抗原 (EBNA) 基因。在 DLBCL 患者 (332 bp) 中發(fā)現(xiàn)的 Cp 缺失被引入 B95-8 菌株的 EBV-BAC。有趣的是，dCp 病毒比 WT 和回復(fù)毒株更有效地轉(zhuǎn)化 B 細(xì)胞。Cp 的刪除也促進(jìn)了小鼠異種移植模型中的腫瘤形成和嚴(yán)重的致病性。RNA 測(cè)序和 qRT-PCR 分析顯示，在 dCp 細(xì)胞中檢測(cè)不到 Cp 轉(zhuǎn)錄。相反，從 W 啟動(dòng)子 (Wp) 的轉(zhuǎn)錄，EBNA 的替代啟動(dòng)子，在 dCp 突變體中被激活。我們還發(fā)現(xiàn)潛伏膜蛋白 2A (LMP2A) 的表達(dá)在 dCp 突變體中以某種方式被誘導(dǎo)。Cp和LMP2A的雙重敲除表明LMP2A對(duì)B細(xì)胞轉(zhuǎn)化至關(guān)重要，但Cp缺失誘導(dǎo)的轉(zhuǎn)化增加不能單獨(dú)用LMP2A解釋。我們還測(cè)試了抗凋亡病毒 BCL2 同源物 BHRF1 的作用，因?yàn)閾?jù)報(bào)道它的表達(dá)被 Wp 更有效地誘導(dǎo)。然而，通過 Cp 缺失增加的生長(zhǎng)轉(zhuǎn)化不是由于 BHRF1 基因?？傊?，結(jié)果表明，刪除 Cp 中的特定區(qū)域會(huì)增加體外轉(zhuǎn)化和體內(nèi) EBV 陽性淋巴增殖性疾病的進(jìn)展速度。我們的數(shù)據(jù)表明，不僅宿主的基因組改變，而且病毒的基因組改變都促進(jìn)了 EBV 陽性腫瘤的產(chǎn)生和擴(kuò)張，盡管這種現(xiàn)象背后的分子機(jī)制仍不清楚。但是，不涉及 LMP2A 和 BHRF1。

PETG血清培養(yǎng)基瓶

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 陽性 DLBCL 中發(fā)現(xiàn)的 Cp 缺失似乎增加了生長(zhǎng)轉(zhuǎn)化效率。雖然這種現(xiàn)象的分子機(jī)制仍然難以捉摸，但部分 EBV 基因的缺失可能會(huì)增加致瘤性。

關(guān)鍵詞： EBV,DLBCL ,C啟動(dòng)子,LMP2A ,BHRF1,成長(zhǎng)轉(zhuǎn)型EBV,DLBCL,C promoter, LMP2A, BHRF1, growth transformation

來源： MDPI https://www.mdpi.com/2072-6694/13/3/561/htm