Transcriptomic Abnormalities in Epstein Barr Virus Associated T/NK Lymphoproliferative Disorders

Abstract

Epstein Barr virus positive T/NK lymphoproliferative disorders (EBV-TNKLPD) comprise a spectrum of neoplasms ranging from cutaneous lymphoid proliferations to aggressive lymphomas. The spectrum includes extranodal NK/T-cell lymphoma (ENKTL), aggressive NK-cell leukemia, and a group of EBV-TNKLPDs affecting children which are poorly characterized in terms of their molecular biology. Gene and miRNA expression profiling has elucidated RNA abnormalities which impact on disease biology, classification, and treatment of EBV-TNKLPD. Pathways promoting proliferation, such as Janus associated kinase/ Signal Transducer and Activator of Transcription (JAK/STAT) and nuclear factor kB, are upregulated in ENKTL while upregulation of survivin and deregulation of p53 inhibit apoptosis in both ENKTL and chronic active EBV infection (CAEBV). Importantly, immune evasion via the programmed cell death-1 and its ligand, PD-1/PD-L1 checkpoint pathway, has been demonstrated to play an important role in ENKTL. Other pathogenic mechanisms involve EBV genes, microRNA deregulation, and a variety of other oncogenic signaling pathways. The identification of EBV-positive Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) as a tumor with a distinct molecular signature and clinical characteristics highlights the important contribution of the knowledge derived from gene and miRNA expression profiling in disease classification. Novel therapeutic targets identified through the study of RNA abnormalities provide hope for patients with EBV-TNKLPD, which often has a poor prognosis. Immune checkpoint inhibition and JAK inhibition in particular have shown promise and are being evaluated in clinical trials. In this review, we provide an overview of the key transcriptomic aberrancies in EBV-TNKLPD and discuss their translational potential.

Icaritin inhibits PLK1 to activate DNA damage response in NK/T cell lymphoma and increases sensitivity to GELOX regime

“…11 However, DDR is defective in various kinds of tumors, including NKTCL, making it an important antitumor target. 7 Consistently, a previous study of our team found that part of the DDR pathway was hindered midway in NKTCL tissues, with ATM overactivated while its downstream factors Chk2 and p53 unactivated, compared with the normal tissues. 17 The DDR defect also creates vulnerabilities in tumors and has been exploited as a target of antitumor therapy.…”

“…6 The pathogenesis of NKTCL has not been fully understood, but the deregulation of the DNA damage response (DDR) may play a role. 7 DNA lesions occur constantly owing to the assaults of endogenous metabolites and environmental stressors. In response to DNA double-strand breaks (DSBs), the immediate-early sensors ataxia telangiectasia mutated (ATM) activates and then phosphorylates checkpoint kinase 2 (Chk2) on its Thr68 site.…”

Metagenomic Next-Generation Sequencing of Bloodstream Microbial Cell-Free Nucleic Acid in Children With Suspected Sepsis in Pediatric Intensive Care Unit

“…EBV can cause latent infection: when an infected individual develops an immunosuppressive state, it is reactivated, which can lead to infectious mononucleosis, lymphoma, and lymphoproliferative diseases. EBV reactivation is very common after kidney transplantation and is associated with increased morbidity and mortality ( Cohen, 2000 ; Blazquez-Navarro et al., 2018 ; de Mel et al., 2018 ). In the present study, we found that the abundance of bloodstream EBV in children in PICU was positively correlated with lymphocyte subtype counts, including WBC, CD4+ T cells, CD3+ T cells, and CD8+ T cells.…”

Hydroa vacciniforme-like lymphoproliferative disorder: A study of clinicopathology and whole-exome sequencing in Chinese patients

“…In recent years, many scholars have made important contributions to research in EBV-related lymphoproliferative diseases, leading to breakthroughs in genomic exploration. Nonetheless, relevant studies have mostly focused on EBV T/natural killer (NK) cell lymphoproliferative diseases or chronic active EBV (CAEBV) infection [7][8][9][10], and sequencing for HVLPD has rarely been performed. HVLPD shares many common features with EBV T/NK cell lymphoproliferative diseases or CAEBV without HVLPD, including high levels of EBV DNA in the blood (primarily inTor NK cells) and a high frequency of clonal T cells.…”