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Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. The disease is very heterogeneous, with distinct genetic alterations in subtypes. The WHO 2022 5th edition classification identifies several minor groups of large B-cell lymphoma where the pathogenetic role of viruses (like EBV and HHV-8) is identified. Still, most cases fall into the group of DLBCL not otherwise specified (NOS). No review focuses only on this specific lymphoma type in the literature. The pathogenesis of this entity is still not fully understood, but several viruses and bacteria may have a role in the development of the disease. The authors review critical pathogenetic events in the development of DLBCL (NOS) and summarize the data available on several pathogenetic viruses and bacteria that have a proven or may have a potential role in the development of this lymphoma type. The possible role of B-cell receptor signaling in the microenvironment is also discussed. The causative role of the Epstein–Barr virus (EBV), human herpesvirus-8 (HHV-8), Hepatitis C virus (HCV), human immunodeficiency virus (HIV), Hepatitis B virus (HBV), and other viruses are explored. Bacterial infections, such as Helicobacter pylori, Campylobacter jejuni, Chlamydia psittaci, Borrelia burgdorferi, and other bacteria, are also reviewed. [ABSTRACT FROM AUTHOR]

CD30-positive germinal center (GC)-derived B cell lymphomas are frequently linked to Epstein–Barr Virus (EBV) infection. However, a suitable animal model for the investigation of the interplay between γ-herpesvirus and host cells in B cell pathogenesis is currently lacking. Here, we present a novel in vivo model enabling the analysis of genetically modified viruses in combination with genetically modified GC B cells. As a murine γ-herpesvirus, we used MHV-68 closely mirroring the biology of EBV. Our key finding was that Cre-mediated recombination can be successfully induced by an MHV-68 infection in GC B cells from Cγ1-Cre mice allowing for deletion or activation of loxP-flanked cellular genes. The implementation of PrimeFlow RNA assay for MHV-68 demonstrated the enrichment of MHV-68 in GC and isotype-switched B cells. As illustrations of virus and cellular modifications, we inserted the EBV gene LMP2A into the MHV-68 genome and induced constitutively active CD30-signaling in GC B cells through MHV-68 infections, respectively. While the LMP2A-expressing MHV-68 behaved similarly to wildtype MHV-68, virally induced constitutively active CD30-signaling in GC B cells led to the expansion of a pre-plasmablastic population. The findings underscore the potential of our novel tools to address crucial questions about the interaction between herpesviral infections and deregulated cellular gene-expression in future studies. [ABSTRACT FROM AUTHOR]

Lymphomas are a heterogeneous group of pathologies that result from clonal proliferation of lymphocytes. They are classified into Hodgkin lymphoma and non-Hodgkin lymphoma; the latter develops as a result of B, T, or NK cells undergoing malignant transformation. It is believed that diet can modulate cellular redox state and that oxidative stress is implicated in lymphomagenesis by acting on several biological mechanisms; in fact, oxidative stress can generate a state of chronic inflammation through the activation of various transcription factors, thereby increasing the production of proinflammatory cytokines and causing overstimulation of B lymphocytes in the production of antibodies and possible alterations in cellular DNA. The purpose of our work is to investigate the results of in vitro and in vivo studies on the possible interaction between lymphomas, oxidative stress, and diet. A variety of dietary regimens and substances introduced with the diet that may have antioxidant and antiproliferative effects were assessed. The possibility of using nutraceuticals as novel anticancer agents is discussed; although the use of natural substances in lymphoma therapy is an interesting field of study, further studies are needed to define the efficacy of different nutraceuticals before introducing them into clinical practice. [ABSTRACT FROM AUTHOR]

Simple Summary: The Epstein–Barr virus is a human herpesvirus that infects the majority of the human population. Initially, infection can cause mild symptoms in infants and children, but can also cause short-lived infectious mononucleosis in teenage and young adults. But, in a small minority of older patients, persistent expression of virus antigens can cause B cell transformation to a cancer. Patients with Epstein–Barr virus-positive B cell lymphoma are often more resistant to treatment with standard chemotherapy. One difficulty in developing new methods of treatment is that Epstein–Barr only infects human cells, and there are no mouse B cell models of the disease. Our goal was to develop a mouse model of disease, in order to study the potential for effective vaccination against an Epstein–Barr virus antigen. We were successful in generating a mouse B cell line expressing latent membrane protein 1, and could show that vaccination protected mice against B cell tumors that expressed latent membrane protein 1. This system will allow us to further study the potential for vaccination in patients with cancer, to help the immune system recognize and eliminate tumor cells. In this study, we demonstrate that expression of viral latent membrane protein 1 (LMP1) in a mouse B cell line renders the animals responsive to protection from a 38C13-LMP1 tumor challenge with a novel vaccine. The Epstein–Barr virus (EBV) preferentially infects circulating B lymphocytes, has oncogenic potential, and is associated with a wide variety of B cell lymphomas. EBV is ectotrophic to human cells, and currently there are no B cell animal models of EBV-associated lymphoma that can be used to investigate vaccine immunotherapy. Since most EBV-infected human tumor cells express latent membrane protein 1 (LMP1) on their surface, this viral antigen was tested as a potential target for an anticancer vaccine in a mouse model. Here, we describe a new mouse model of LMP1-expressing B cell lymphoma produced with plasmid transduction of 38C13 into mouse B cells. The expression of LMP-1 was confirmed with a western blot analysis and immunocytochemistry. We then designed a novel LMP1 vaccine, by fusing viral antigen LMP1 surface loop epitopes to the surface of a viral antigen carrier, the Tobacco Mosaic virus (TMV). Vaccinated mice produced high titer antibodies against the TMV-LMP1 vaccine; however, cellular responses were at the baseline, as measured with IFNγ ELISpot. Despite this, the vaccine showed significant protection from a 38C13-LMP1 tumor challenge. To provide additional immune targets, we compared TMV-LMP1 peptide immunization with DNA immunization with the full-length LMP1 gene. Anti-LMP1 antibodies were significantly higher in TMV-LMP1-vaccinated mice compared to the DNA-immunized mice, but, as predicted, DNA-vaccinated mice had improved cellular responses using IFNγ ELISpot. Surprisingly, the TMV-LMP1 vaccine provided protection from a 38C13-LMP1 tumor challenge, while the DNA vaccine did not. Thus, we demonstrated that LMP1 expression in a mouse B cell line is responsive to antibody immunotherapy that may be applied to EBV-associated disease. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV), defined as a group I carcinogen by the World Health Organization (WHO), is present in the tumour cells of patients with different forms of B-cell lymphoma, including Burkitt lymphoma, Hodgkin lymphoma, post-transplant lymphoproliferative disorders, and, most recently, diffuse large B-cell lymphoma (DLBCL). Understanding how EBV contributes to the development of these different types of B-cell lymphoma has not only provided fundamental insights into the underlying mechanisms of viral oncogenesis, but has also highlighted potential new therapeutic opportunities. In this review, we describe the effects of EBV infection in normal B-cells and we address the germinal centre model of infection and how this can lead to lymphoma in some instances. We then explore the recent reclassification of EBV+ DLBCL as an established entity in the WHO fifth edition and ICC 2022 classifications, emphasising the unique nature of this entity. To that end, we also explore the unique genetic background of this entity and briefly discuss the potential role of the tumour microenvironment in lymphomagenesis and disease progression. Despite the recent progress in elucidating the mechanisms of this malignancy, much work remains to be done to improve patient stratification, treatment strategies, and outcomes. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV) is an oncogenic human herpesvirus infecting approximately 90% of the world's population. The oral cavity serves a central role in the life cycle, transmission, and pathogenesis of EBV. Transmitted to a new host via saliva, EBV circulates between cellular compartments within oral lymphoid tissues. Epithelial cells primarily support productive viral replication, while B lymphocytes support viral latency and reactivation. EBV infections are typically asymptomatic and benign; however, the latent virus is associated with multiple lymphomas and carcinomas arising in the oral cavity. EBV association with cancer is complex as histologically similar cancers often test negative for the virus. However, the presence of EBV is associated with distinct features in certain cancers. The intrinsic ability of EBV to immortalize B-lymphocytes, via manipulation of survival and growth signaling, further implicates the virus as an oncogenic cofactor. A distinct mutational profile and burden have been observed in EBV-positive compared to EBV-negative tumors, suggesting that viral infection can drive alternative pathways that converge on oncogenesis. Taken together, EBV is also an important prognostic biomarker that can direct alternative therapeutic approaches. Here, we discuss the prevalence of EBV in oral malignancies and the EBV-dependent mechanisms associated with tumorigenesis. [ABSTRACT FROM AUTHOR]

Simple Summary: Chronic lymphocytic leukemia (CLL) cells in the peripheral blood and lymphoid microenvironment display substantially different gene expression profiles and proliferative capaci-ty. It has been suggested that CLL–T-cell interactions are key pro-proliferative stimuli in immune niches. We review in vitro and in vivo model systems that mimic CLL-T-cell interactions to trigger CLL proliferation and study therapy resistance. We focus on studies describing the co-culture of leukemic cells with T cells, or supportive cell lines expressing T-cell factors, and simplified models of CLL cells' stimulation with recombinant factors. In the second part, we summarize mouse models revealing the role of T cells in CLL biology and implications for generating patient-derived xenografts by co-transplanting leukemic cells with T cells. T cells are key components in environments that support chronic lymphocytic leukemia (CLL), activating CLL-cell proliferation and survival. Here, we review in vitro and in vivo model systems that mimic CLL–T-cell interactions, since these are critical for CLL-cell division and resistance to some types of therapy (such as DNA-damaging drugs or BH3-mimetic venetoclax). We discuss approaches for direct CLL-cell co-culture with autologous T cells, models utilizing supportive cell lines engineered to express T-cell factors (such as CD40L) or stimulating CLL cells with combinations of recombinant factors (CD40L, interleukins IL4 or IL21, INFγ) and additional B-cell receptor (BCR) activation with anti-IgM antibody. We also summarize strategies for CLL co-transplantation with autologous T cells into immunodeficient mice (NOD/SCID, NSG, NOG) to generate patient-derived xenografts (PDX) and the role of T cells in transgenic CLL mouse models based on TCL1 overexpression (Eµ-TCL1). We further discuss how these in vitro and in vivo models could be used to test drugs to uncover the effects of targeted therapies (such as inhibitors of BTK, PI3K, SYK, AKT, MEK, CDKs, BCL2, and proteasome) or chemotherapy (fludarabine and bendamustine) on CLL–T-cell interactions and CLL proliferation. [ABSTRACT FROM AUTHOR]

Simple Summary: Endemic Burkitt lymphoma is an aggressive pediatric cancer whose etiological factors include Epstein–Barr virus (EBV) infection and malaria or environmental carcinogen exposures, such as aflatoxin B1 (AFB1). As evidence suggests B cell methylome remodeling to be a transformation mechanism shared by both EBV and AFB1, the identification of a common molecular signature compromising cell fate could reveal an essential driver of lymphomagenesis and provide a relevant target for novel therapies. We, therefore, explored the genome-wide DNA methylation profiles associated with both endemic Burkitt lymphoma and AFB1 exposure and identified a shared signature affecting the expression of a putative tumor suppressor, TGFBI, whose reduced expression has already been investigated in several cancers, but whose implication in lymphoma has not been evidenced so far. Further research clarifying the functional consequence of TGFBI suppression on B cell fate and the impact on tumor microenvironment reshaping is warranted. Burkitt lymphoma (BL) is a malignant B cell neoplasm that accounts for almost half of pediatric cancers in sub-Saharan African countries. Although the BL endemic prevalence is attributable to the combination of Epstein–Barr virus (EBV) infection with malaria and environmental carcinogens exposure, such as the food contaminant aflatoxin B1 (AFB1), the molecular determinants underlying the pathogenesis are not fully understood. Consistent with the role of epigenetic mechanisms at the interface between the genome and environment, AFB1 and EBV impact the methylome of respectively leukocytes and B cells specifically. Here, we conducted a thorough investigation of common epigenomic changes following EBV or AFB1 exposure in B cells. Genome-wide DNA methylation profiling identified an EBV–AFB1 common signature within the TGFBI locus, which encodes for a putative tumor suppressor often altered in cancer. Subsequent mechanistic analyses confirmed a DNA-methylation-dependent transcriptional silencing of TGFBI involving the recruitment of DNMT1 methyltransferase that is associated with an activation of the NF-κB pathway. Our results reveal a potential common mechanism of B cell transformation shared by the main risk factors of endemic BL (EBV and AFB1), suggesting a key determinant of disease that could allow the development of more efficient targeted therapeutic strategies. [ABSTRACT FROM AUTHOR]

The Epstein–Barr virus (EBV) is a well-adapted human virus, and its infection is exclusive to our species, generally beginning in the childhood and then persisting throughout the life of most of the affected adults. Although this infection generally remains asymptomatic, EBV can trigger life-threatening conditions under unclear circumstances. The EBV lifecycle is characterized by interactions with other viruses or bacteria, which increases the probability of awakening its pathobiont capacity. For instance, EBV infects B cells with the potential to alter the germinal center reaction (GCR)—an adaptive immune structure wherein mutagenic-driven processes take place. HIV- and Plasmodium falciparum-induced B cell hyperactivation also feeds the GCR. These agents, along with the B cell tropic KSHV, converge in the ontogeny of germinal center (GC) or post-GC lymphomas. EBV oral transmission facilitates interactions with local bacteria and HPV, thereby increasing the risk of periodontal diseases and head and neck carcinomas. It is less clear as to how EBV is localized in the stomach, but together with Helicobacter pylori, they are known to be responsible for gastric cancer. Perhaps this mechanism is reminiscent of the local inflammation that attracts different herpesviruses and enhances graft damage and chances of rejection in transplanted patients. In this review, we discussed the existing evidence suggestive of EBV possessing the potential to synergize or cooperate with these agents to trigger or worsen the disease. [ABSTRACT FROM AUTHOR]

Lymphocyte migration to and sequestration in specific microenvironments plays a crucial role in their differentiation and survival. Lymphocyte trafficking and homing are tightly regulated by signaling pathways and is mediated by cytokines, chemokines, cytokine/chemokine receptors and adhesion molecules. The production of cytokines and chemokines is largely controlled by transcription factors in the context of a specific epigenetic landscape. These regulatory factors are strongly interconnected, and they influence the gene expression pattern in lymphocytes, promoting processes such as cell survival. The epigenetic status of the genome plays a key role in regulating gene expression during many key biological processes, and it is becoming more evident that dysregulation of epigenetic mechanisms contributes to cancer initiation, progression and drug resistance. Here, we review the signaling pathways that regulate lymphoma cell migration and adhesion with a focus on Mantle cell lymphoma and highlight the fundamental role of epigenetic mechanisms in integrating signals at the level of gene expression throughout the genome. [ABSTRACT FROM AUTHOR]

Simple Summary: Epstein-Barr Virus (EBV)-induced lymphomas have a significant global incidence, given the widespread infection to the human population. EBV adopts several mechanisms to replicate and persist in the host, by hijacking its epigenetic machinery. The main topic of this review details the current insights of EBV interactions with the host epigenetic system, and it will be discussed the potential relationship between the EBV-induced chronic inflammation and the dysregulation of epigenetic modifiers that might lead to tumorigenesis. Promising novel therapies against several types of cancer involve the use of epigenetic modifier inhibitors. To design new therapeutical strategies targeting lymphomas, it is crucial to conduct exhaustive reaserch on the regulation of these enzymes. During the past decade, the rapid development of high-throughput next-generation sequencing technologies has significantly reinforced our understanding of the role of epigenetics in health and disease. Altered functions of epigenetic modifiers lead to the disruption of the host epigenome, ultimately inducing carcinogenesis and disease progression. Epstein–Barr virus (EBV) is an endemic herpesvirus that is associated with several malignant tumours, including B-cell related lymphomas. In EBV-infected cells, the epigenomic landscape is extensively reshaped by viral oncoproteins, which directly interact with epigenetic modifiers and modulate their function. This process is fundamental for the EBV life cycle, particularly for the establishment and maintenance of latency in B cells; however, the alteration of the host epigenetic machinery also contributes to the dysregulated expression of several cellular genes, including tumour suppressor genes, which can drive lymphoma development. This review outlines the molecular mechanisms underlying the epigenetic manipulation induced by EBV that lead to transformed B cells, as well as novel therapeutic interventions to target EBV-associated B-cell lymphomas. [ABSTRACT FROM AUTHOR]

Simple Summary: Epstein-Barr virus (EBV) is the first-discovered and important human tumor virus. It infects more than 90% of human population and induces various lymphomas. Development of specific targeted therapies is very critical for treatment of EBV-induced lymphomas, but it remains a great challenge. In this review, we introduced the current progress of EBV-specific therapies and the promising approaches that can be developed as novel targeted therapies, which involve protective or therapeutic strategies to target these lymphomas on different levels. This work will provide new insights into the development of new targeted therapies against EBV-associated lymphomas. The Epstein-Barr virus (EBV) is the first human tumor virus identified that can transform quiescent B lymphocytes into lymphoblastoid cell lines (LCLs) in vitro. EBV can establish asymptomatic life-long persistence and is associated with multiple human malignancies, including non-Hodgkin lymphoma and Hodgkin lymphoma, as well as infectious mononucleosis. Although EBV-associated lymphomagenesis has been investigated for over 50 years, viral-mediated transformation is not completely understood, and the development of EBV-specific therapeutic strategies to treat the associated cancers is still a major challenge. However, the rapid development of several novel therapies offers exciting possibilities to target EBV-induced lymphomas. This review highlights targeted therapies with potential for treating EBV-associated lymphomas, including small molecule inhibitors, immunotherapy, cell therapy, preventative and therapeutic vaccines, and other potent approaches, which are novel strategies for controlling, preventing, and treating these viral-induced malignances. [ABSTRACT FROM AUTHOR]

The Epstein-Barr virus (EBV) is present in the tumour cells of a subset of patients with classic Hodgkin lymphoma (cHL), yet the contribution of the virus to the pathogenesis of these tumours remains only poorly understood. The EBV genome in virus-associated cHL expresses a limited subset of genes, restricted to the non-coding Epstein-Barr virus-encoded RNAs (EBERs) and viral miRNA, as well as only three virus proteins; the Epstein-Barr virus nuclear antigen-1 (EBNA1), and the two latent membrane proteins, known as LMP1 and LMP2, the latter of which has two isoforms, LMP2A and LMP2B. LMP1 and LMP2A are of particular interest because they are co-expressed in tumour cells and can activate cellular signalling pathways, driving aberrant cellular transcription in infected B cells to promote lymphomagenesis. This article seeks to bring together the results of recent studies of the latent membrane proteins in different B cell systems, including experiments in animal models as well as a re-analysis of our own transcriptional data. In doing so, we summarise the potentially co-operative and antagonistic effects of the LMPs that are relevant to B cell lymphomagenesis. [ABSTRACT FROM AUTHOR]

Pathogenic viruses have evolved to manipulate the host cell utilising a variety of strategies including expression of viral proteins to hijack or mimic the activity of cellular functions. DNA tumour viruses often establish latent infection in which no new virions are produced, characterized by the expression of a restricted repertoire of so-called latent viral genes. These latent genes serve to remodel cellular functions to ensure survival of the virus within host cells, often for the lifetime of the infected individual. However, under certain circumstances, virus infection may contribute to transformation of the host cell; this event is not a usual outcome of infection. Here, we review how the Epstein–Barr virus (EBV), the prototypic oncogenic human virus, modulates host cell functions, with a focus on the role of the EBV latent genes in classical Hodgkin lymphoma. [ABSTRACT FROM AUTHOR]