INSERM U1163/CNRS ERL8254 - Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Institut Imagine, Paris, France.
Hub de Bioinformatique et Biostatistique - Département Biologie Computationnelle, Institut Pasteur, Paris, France.
Orphanet J Rare Dis. 2021 Jun 28;16(1):288. doi: 10.1186/s13023-021-01904-3.
Epstein-Barr virus (EBV) targets B-cells where it establishes a latent infection. EBV can transform B-cells in vitro and is recognized as an oncogenic virus, especially in the setting of immune compromise. Indeed, immunodeficient patients may fail to control chronic EBV infection, leading to the development EBV-driven lymphoid malignancies. Ataxia telangiectasia (AT) is a primary immune deficiency caused by mutations in the ATM gene, involved in the repair of double-strand breaks. Patients with AT are at high risk of developing cancers, mostly B-cell lymphoid malignancies, most of which being EBV-related. Aside from immune deficiency secondary to AT, loss of ATM function could also hinder the control of the virus within B-cells, favoring lymphomagenesis in AT patients.
We used RNA sequencing on lymphoblastoid cell lines derived from patients with AT and healthy donors to analyze and compare both cellular and viral gene expression. We found numerous deregulated signaling pathways involving transcription, translation, oncogenesis and immune regulation. Specifically, the translational defect was confirmed in vitro, suggesting that the pathogenesis of AT may also involve a ribosomal defect. Concomitant analysis of viral gene expression did not reveal significant differential gene expression, however, analysis of EBV interactome suggests that the viral latency genes EBNA-3A, EBNA-3C and LMP1 may be disrupted in LCL from AT patients.
Our data support the notion that ATM deficiency deregulates cellular gene expression possibly disrupting interactions with EBV latent genes, promoting the oncogenic potential of the virus. These preliminary findings provide a new step towards the understanding of EBV regulation and of AT pathogenesis.
EB 病毒（EBV）靶向 B 细胞，并在其中建立潜伏感染。EBV 可在体外转化 B 细胞，被认为是一种致癌病毒，尤其是在免疫受损的情况下。事实上，免疫缺陷患者可能无法控制慢性 EBV 感染，导致 EBV 驱动的淋巴恶性肿瘤的发展。共济失调毛细血管扩张症（AT）是一种由 ATM 基因突变引起的原发性免疫缺陷病，该基因参与双链断裂的修复。AT 患者患癌症的风险很高，主要是 B 细胞淋巴恶性肿瘤，其中大多数与 EBV 相关。除了由于 AT 导致的免疫缺陷外，ATM 功能的丧失也可能阻碍 EBV 在 B 细胞内的控制，有利于 AT 患者的淋巴瘤发生。
我们使用来自 AT 患者和健康供体的淋巴母细胞系进行 RNA 测序，以分析和比较细胞和病毒基因表达。我们发现了许多涉及转录、翻译、致癌和免疫调节的失调信号通路。具体来说，体外证实了翻译缺陷，这表明 AT 的发病机制也可能涉及核糖体缺陷。同时分析病毒基因表达并未显示出显著的差异基因表达，但 EBV 相互作用体的分析表明，EBV 潜伏基因 EBNA-3A、EBNA-3C 和 LMP1 可能在 AT 患者的 LCL 中受到破坏。
我们的数据支持这样一种观点，即 ATM 缺陷会使细胞基因表达失调，可能破坏与 EBV 潜伏基因的相互作用，从而促进病毒的致癌潜力。这些初步发现为理解 EBV 调控和 AT 发病机制提供了新的研究方向。
