Epstein-Barr Virus (EBV)-Related Lymphoproliferative Disorders in Ataxia Telangiectasia: Does ATM Regulate EBV Life Cycle?

Abstract

Epstein-Barr virus (EBV) is an ubiquitous herpesvirus with a tropism for epithelial cells (where lytic replication occurs) and B-cells (where latency is maintained). EBV persists throughout life and chronic infection is asymptomatic in most individuals. However, immunocompromised patients may be unable to control EBV infection and are at increased risk of EBV-related malignancies, such as diffuse large B-cell lymphomas or Hodgkin's lymphomas. Ataxia telangiectasia (AT) is a primary immunodeficiency caused by mutations in the ATM gene and associated with an increased incidence of cancers, particularly EBV-associated lymphomas. However, the immune deficiency present in AT patients is often too modest to explain the increased incidence of EBV-related malignancies. The ATM defect in these patients could therefore impair the normal regulation of EBV latency in B-cells, thus promoting lymphomagenesis. This suggests that ATM plays a role in the normal regulation of EBV latency. ATM is a serine/threonine kinase involved in multiple cell functions such as DNA damage repair, cell cycle regulation, oxidative stress, and gene expression. ATM is implicated in the lytic cycle of EBV, where EBV uses the activation of DNA damage repair pathway to promote its own replication. ATM regulates the latent cycle of the EBV-related herpesvirus KSHV and MHV68. However, the contribution of ATM in the control of the latent cycle of EBV is not yet known. A better understanding of the regulation of EBV latency could be harnessed in the conception of novel therapeutic strategies in AT and more generally in all ATM deficient EBV-related malignancies.

Granulomatous Liver Disease in Ataxia-Telangiectasia With the Hyper-IgM Phenotype: A Case Report

“…In the patient studied, two episodes of EBV-DNA in blood were revealed, supporting other reports of increased susceptibility to EBV in A-T, resulting from thymic insufficiency and a defective generation of naïve T helper cells, leading to further impaired interferon-gamma (IFN-γ) production and a failure to antiviral defense mechanisms. Furthermore, ATM kinase participates in the control of chronic EBV infection, playing a role in the regulation of viral latency, contributing to the EBV-induced lymphomagenesis in A-T (25). However, the potential significance of the latent cycle of EBV in A-T and ATM deficiency in granulomatous disease has not been explored and remains a subject for further research.…”

Gene expression analysis in EBV-infected ataxia-telangiectasia cell lines by RNA-sequencing reveals protein synthesis defect and immune abnormalities

“…Mechanisms associated with this specific susceptibility may be due cellular immune deficiency in a number of AT patients, or to other specific immune dysfunctions that remain to be explored. We raised the hypothesis that ATM defect in EBV-infected cells could play a role per se in the control of EBV latency, favoring a latent program more prone to lymphomagenesis [ 19 ]. In the present study, we used strand-specific RNA seq strategy to profile the RNA expression landscape of ATM deficient LCL versus control, in order to assess the involvement of ATM in EBV latent cycle regulation.…”

Clinical complications and their management in a child with ataxia‐telangiectasia (A‐T): A case report study

“…Moreover, various infections are responsible for its morbidity and mortality 6 . The ATM gene codes for a ATM serine/threonine kinase, which is recruited and activated by DNA double‐strand breaks, and plays a pivotal role in the reconstruction of fractured DNA during the differentiation and development of the cells such as B and T cells 7,8 . In addition to the role of ATM mutations in susceptibility to A‐T, genetic variations in this gene contribute to the development of different cancers such as lymphoma and breast cancer 7,9 .…”

“…6 The ATM gene codes for a ATM serine/threonine kinase, which is recruited and activated by DNA double-strand breaks, and plays a pivotal role in the reconstruction of fractured DNA during the differentiation and development of the cells such as B and T cells. 7,8 In addition to the role of ATM mutations in susceptibility to A-T, genetic variations in this gene contribute to the development of different cancers such as lymphoma and breast cancer. 7,9 Some relationships have been reported between A-T and other disorders such as hyperimmunoglobulin (HIgM) syndrome and dystonia, 10 but the associations of A-T with other disorders are not well identified yet.…”