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The Epstein-Barr virus (EBV) is a known oncogenic virus associated with various lymphoma subtypes throughout the world. However, there is a lack of information regarding EBV prevalence in lymphoma patients, specifically in Ethiopia. This study aimed to investigate the presence of the EBV and determine its viral load in lymphoma patients from Ethiopia using molecular and serological approaches. Lymphoma patient samples were collected from the Ethiopian population. DNA and serum samples were extracted and subjected to molecular detection methods, including quantitative polymerase chain reaction (qPCR) analysis targeting the EBNA1 gene. Serological analyses were performed using an enzyme-linked immunosorbent assay (ELISA) to detect EBV viral capsid antigen IgG antibodies. EBV DNA was detected in 99% of lymphoma patients using qPCR, and serological analyses showed EBV presence in 96% of cases. A high EBV viral load (>10,000 EBV copies/mL) was observed in 56.3% of patients. The presence of high EBV viral loads was observed in 59.3% of HL patients and 54.8% of NHL patients. This study provides important insights into the prevalence and viral load of the EBV among lymphoma patients in Ethiopia. The findings contribute to the limited knowledge in this area and can serve as a foundation for future research. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV) is an oncogenic herpes virus associated with several human malignancies. Two main EBV genotypes (type 1 and type 2) distinguished by the differences in EBV nuclear antigens are known. Geographic variability in these genetic differences has been observed in the incidence of some EBV-related tumors. Here, we investigated the genetic variation of EBV in lymphoma specimens collected in Ethiopia. A total of 207 DNA samples were used for EBV detection and typing, and EBNA1 and EBNA3C genes were used to detect and subtype the EBV genome, respectively. EBV genotype 1 was detected in 52.2% of lymphoma patients. EBV genotype 2 was detected in 38.2% of the lymphoma patients, and 9.7% were coinfected by both EBV genotypes. Overall, 52.8% of the Hodgkin's lymphoma (HL) patients and 51.8% of non-Hodgkin's lymphoma (NHL) patients showed the presence of genotype 1. Meanwhile, 42.8% and 2.3% of HL patients and 35.8% and 12.4% of NHL patients showed EBV genotype 2 and both genotypes, respectively. Significant associations between the age groups and EBV genotypes were observed (p = 0.027). However, no significant association was seen between EBV genotypes and other sociodemographic and clinical characteristics. This study showed that the distribution of EBV genotype 1 was higher in Ethiopian lymphoma patients. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV) is a well-known risk factor for the development of nasopharyngeal carcinoma, Hodgkin's lymphoma (HL), and Non-Hodgkin's lymphoma (NHL). People with HIV infection (PWH) are at increased risk for EBV-associated malignancies such as HL and NHL. Nevertheless, there are limited data on the burden of EBV among this population group in Ethiopia. Hence, this study aimed to determine the burden of EBV infection among adult HIV-positive individuals in Ethiopia and assess the determinants of EBV DNA positivity. We conducted a cross-sectional study at the Tikur Anbessa Specialised Hospital from March 2020 to March 2021. Two hundred and sixty individuals were enrolled in this study, including 179 HIV-positive and 81 HIV-negative individuals. A structured questionnaire was used to capture demographic and individual attributes. In addition, the clinical data of patients were also retrieved from clinical records. EBV viral capsid antigen (VCA) IgG antibody was measured by multiplex flow immunoassay, and EBV DNA levels were tested by quantitative real-time polymerase chain reaction (q-PCR) assays targeting the EBNA-1 open reading frame (ORF). Descriptive statistics were conducted to assess each study variable. A multivariable logistic regression model was applied to evaluate the determinants of EBV infection. Statistical significance was determined at a p-value < 0.05. Two hundred and fifty-three (97.7%) study participants were seropositive for the EBV VCA IgG antibody. Disaggregated by HIV status, 99.4% of HIV-positive and 93.8% of HIV-negative participants were EBV seropositive. In this study, 49.7% of HIV-positive and 24.7% of HIV-negative individuals were EBV DNA positive. PWH had a higher risk of EBV DNA positivity at 3.05 times (AOR: 3.05, 95% CI: 1.40–6.67). Moreover, among PWH, those with an HIV viral load greater than 1000 RNA copies/mL (AOR = 5.81, 95% CI = 1.40, 24.13) had a higher likelihood of EBV DNA positivity. The prevalence of EBV among PWH was significantly higher than among HIV-negative individuals. Higher HIV viral loads in PWH were associated with an increased risk of EBV DNA positivity. Since the increases in the viral load of EBV DNA among PWH could be related to the risk of developing EBV-associated cancers, it is necessary for more research on the role of EBV in EBV-associated cancer in this population group to be carried out. [ABSTRACT FROM AUTHOR]

Simple Summary: Relapsed or refractory classical Hodgkin lymphoma remains a difficult treatment challenge. Despite responses with the checkpoint inhibitors nivolumab and pembrolizumab, patients eventually progress. Combining other treatments with checkpoint inhibitors may provide more frequent and durable responses in this setting. We conducted a phase II study in relapsed or refractory Hodgkin lymphoma combining nivolumab with the Bruton's tyrosine kinase inhibitor ibrutinib. Although we did not find an increase in the response rate of this combination compared to that previously reported, responses tended to be durable even in patients who progressed on nivolumab therapy prior to enrollment. Larger studies combining Bruton's tyrosine kinase inhibitors with checkpoint blockade are warranted, especially in patients who had progressed previously on checkpoint inhibitor therapy. Background: Relapsed or refractory classical Hodgkin lymphoma (cHL) remains a difficult treatment challenge. Although checkpoint inhibitors (CPI) have provided clinical benefit for these patients, responses are generally not durable, and progression eventually occurs. Discovering combination therapies which maximize the immune response of CPI therapy may overcome this limitation. We hypothesized that adding ibrutinib to nivolumab will lead to deeper and more durable responses in cHL by promoting a more favorable immune microenvironment leading to enhanced T-cell-mediated anti-lymphoma responses. Methods: We conducted a single arm, phase II clinical trial testing the efficacy of nivolumab in combination with ibrutinib in patients ≥18 years of age with histologically confirmed cHL who had received at least one prior line of therapy. Prior treatment with CPIs was allowed. Ibrutinib was administered at 560 mg daily until progression in combination with nivolumab 3 mg/kg IV every 3 weeks for up to 16 cycles. The primary objective was complete response rate (CRR) assessed per Lugano criteria. Secondary objectives included overall response rate (ORR), safety, progression free survival (PFS), and duration of response (DoR). Results: A total of 17 patients from two academic centers were enrolled. The median age of all patients was 40 (range 20–84). The median number of prior lines of treatment was five (range 1–8), including 10 patients (58.8%) who had progressed on prior nivolumab therapy. Most treatment related events were mild (

Human T-cell leukemia virus type-1 (HTLV-1) is a tumorigenic retrovirus responsible for development of adult T-cell leukemia/lymphoma (ATLL). This disease manifests after a long clinical latency period of up to 2-3 decades. Two viral gene products, Tax and HBZ, have transforming properties and play a role in the pathogenic process. Genetic and epigenetic cellular changes also occur in HTLV-1-infected cells, which contribute to transformation and disease development. However, the role of cellular factors in transformation is not completely understood. Herein, we examined the role of protein arginine methyltransferase 5 (PRMT5) on HTLV-1-mediated cellular transformation and viral gene expression. We found PRMT5 expression was upregulated during HTLV-1-mediated T-cell transformation, as well as in established lymphocytic leukemia/lymphoma cell lines and ATLL patient PBMCs. shRNA-mediated reduction in PRMT5 protein levels or its inhibition by a small molecule inhibitor (PRMT5i) in HTLV-1-infected lymphocytes resulted in increased viral gene expression and decreased cellular proliferation. PRMT5i also had selective toxicity in HTLV-1-transformed T-cells. Finally, we demonstrated that PRMT5 and the HTLV-1 p30 protein had an additive inhibitory effect on HTLV-1 gene expression. Our study provides evidence for PRMT5 as a host cell factor important in HTLV-1-mediated T-cell transformation, and a potential target for ATLL treatment. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) is a human herpes virus that infects over 90% of the world's population and is linked to development of cancer. In immune-competent individuals, EBV infection is mitigated by a highly efficient virus-specific memory T-cell response. Risk of EBV-driven cancers increases with immune suppression (IS). EBV-seronegative recipients of solid organ transplants are at high risk of developing post-transplant lymphoproliferative disease (PTLD) due to iatrogenic IS. While reducing the level of IS may improve EBV-specific immunity and regression of PTLD, patients are at high risk for allograft rejection and need for immune-chemotherapy. Strategies to prevent PTLD in this vulnerable patient population represents an unmet need. We have previously shown that BZLF1-specific cytotoxic T-cell (CTL) expansion following reduced IS correlated with immune-mediated PTLD regression and improved patient survival. We have developed a vaccine to bolster EBV-specific immunity to the BZLF1 protein and show that co-culture of dendritic cells (DCs) loaded with a αDEC205-BZLF1 fusion protein with peripheral blood mononuclear cells (PMBCs) leads to expansion and increased cytotoxic activity of central-effector memory CTLs against EBV-transformed B-cells. Human–murine chimeric Hu-PBL-SCID mice were vaccinated with DCs loaded with αDEC205-BZLF1 or control to assess prevention of fatal human EBV lymphoproliferative disease. Despite a profoundly immunosuppressive environment, vaccination with αDEC205-BZLF1 stimulated clonal expansion of antigen-specific T-cells that produced abundant IFNγ and significantly prolonged survival. These results support preclinical and clinical development of vaccine approaches using BZLF1 as an immunogen to harness adaptive cellular responses and prevent PTLD in vulnerable patient populations. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we present a workflow to understand the modulator of ibrutinib resistance in ABC diffuse large B cell lymphoma by integrating Metabolomics and Gene expression profiling as shown in the graphical abstract. We performed an untargeted metabolomics analysis using a Q-Exactive high-resolution mass spectrometer to dissect the metabolic reprogramming associated with acquired ibrutinib resistance in paired ibrutinib-sensitive and ibrutinib-resistant DLBCL cell lines. Further, we identified common denominators, integrating metabolome and transcriptome data, confirming clinical significance, integrating pathways, and identifying the candidate gene driving ibrutinib resistance and metabolic reprogramming. Our work demonstrates that a multi-omics approach can be a robust and impartial strategy to uncover genes and pathways that cause metabolic deregulation in cancer cells. Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL). B-cell NHLs rely on Bruton's tyrosine kinase (BTK) mediated B-cell receptor signaling for survival and disease progression. However, they are often resistant to BTK inhibitors or soon acquire resistance after drug exposure resulting in the drug-tolerant form. The drug-tolerant clones proliferate faster, have increased metabolic activity, and shift to oxidative phosphorylation; however, how this metabolic programming occurs in the drug-resistant tumor is poorly understood. In this study, we explored for the first time the metabolic regulators of ibrutinib-resistant activated B-cell (ABC) DLBCL using a multi-omics analysis that integrated metabolomics (using high-resolution mass spectrometry) and transcriptomic (gene expression analysis). Overlay of the unbiased statistical analyses, genetic perturbation, and pharmaceutical inhibition was further used to identify the key players contributing to the metabolic reprogramming of the drug-resistant clone. Gene-metabolite integration revealed interleukin four induced 1 (IL4I1) at the crosstalk of two significantly altered metabolic pathways involved in producing various amino acids. We showed for the first time that drug-resistant clones undergo metabolic reprogramming towards oxidative phosphorylation and are modulated via the BTK-PI3K-AKT-IL4I1 axis. Our report shows how these cells become dependent on PI3K/AKT signaling for survival after acquiring ibrutinib resistance and shift to sustained oxidative phosphorylation; additionally, we outline the compensatory pathway that might regulate this metabolic reprogramming in the drug-resistant cells. These findings from our unbiased analyses highlight the role of metabolic reprogramming during drug resistance development. Our work demonstrates that a multi-omics approach can be a robust and impartial strategy to uncover genes and pathways that drive metabolic deregulation in cancer cells. [ABSTRACT FROM AUTHOR]

The increasing number of approved therapies for relapsed mantle cell lymphoma (MCL) provides patients effective treatment options, with increasing complexity in prioritization and sequencing of these therapies. Chemo-immunotherapy remains widely used as frontline MCL treatment with multiple targeted therapies available for relapsed disease. The Bruton's tyrosine kinase inhibitors (BTKi) ibrutinib, acalabrutinib, and zanubrutinib achieve objective responses in the majority of patients as single agent therapy for relapsed MCL, but differ with regard to toxicity profile and dosing schedule. Lenalidomide and bortezomib are likewise approved for relapsed MCL and are active as monotherapy or in combination with other agents. Venetoclax has been used off-label for the treatment of relapsed and refractory MCL, however data are lacking regarding the efficacy of this approach particularly following BTKi treatment. Anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapies have emerged as highly effective therapy for relapsed MCL, with the CAR-T treatment brexucabtagene autoleucel now approved for relapsed MCL. In this review the authors summarize evidence to date for currently approved MCL treatments for relapsed disease including sequencing of therapies, and discuss future directions including combination treatment strategies and new therapies under investigation. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) is a ubiquitous herpes virus associated with various cancers. EBV establishes latency with life-long persistence in memory B-cells and can reactivate lytic infection placing immunocompromised individuals at risk for EBV-driven lymphoproliferative disorders (EBV-LPD). Despite the ubiquity of EBV, only a small percentage of immunocompromised patients (~20%) develop EBV-LPD. Engraftment of immunodeficient mice with peripheral blood mononuclear cells (PBMCs) from healthy EBV-seropositive donors leads to spontaneous, malignant, human B-cell EBV-LPD. Only about 20% of EBV+ donors induce EBV-LPD in 100% of engrafted mice (High-Incidence, HI), while another 20% of donors never generate EBV-LPD (No-Incidence, NI). Here, we report HI donors to have significantly higher basal T follicular helper (Tfh) and regulatory T-cells (Treg), and depletion of these subsets prevents/delays EBV-LPD. Transcriptomic analysis of CD4+ T cells from ex vivo HI donor PBMC revealed amplified cytokine and inflammatory gene signatures. HI vs. NI donors showed a marked reduction in IFNγ production to EBV latent and lytic antigen stimulation. In addition, we observed abundant myeloid-derived suppressor cells in HI donor PBMC that decreased CTL proliferation in co-cultures with autologous EBV+ lymphoblasts. Our findings identify potential biomarkers that may identify individuals at risk for EBV-LPD and suggest possible strategies for prevention.

Human T-cell leukemia virus type-1 (HTLV-1) is a tumorigenic retrovirus responsible for development of adult T-cell leukemia/lymphoma (ATLL). This disease manifests after a long clinical latency period of up to 2-3 decades. Two viral gene products, Tax and HBZ, have transforming properties and play a role in the pathogenic process. Genetic and epigenetic cellular changes also occur in HTLV-1-infected cells, which contribute to transformation and disease development. However, the role of cellular factors in transformation is not completely understood. Herein, we examined the role of protein arginine methyltransferase 5 (PRMT5) on HTLV-1-mediated cellular transformation and viral gene expression. We found PRMT5 expression was upregulated during HTLV-1-mediated T-cell transformation, as well as in established lymphocytic leukemia/lymphoma cell lines and ATLL patient PBMCs. shRNA-mediated reduction in PRMT5 protein levels or its inhibition by a small molecule inhibitor (PRMT5i) in HTLV-1-infected lymphocytes resulted in increased viral gene expression and decreased cellular proliferation. PRMT5i also had selective toxicity in HTLV-1-transformed T-cells. Finally, we demonstrated that PRMT5 and the HTLV-1 p30 protein had an additive inhibitory effect on HTLV-1 gene expression. Our study provides evidence for PRMT5 as a host cell factor important in HTLV-1-mediated T-cell transformation, and a potential target for ATLL treatment.