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1.  The Epstein-Barr virus microRNA BART11-5p targets the early B-cell transcription factor EBF1 
Epstein-Barr virus (EBV) is a ubiquitous B-cell trophic herpesvirus associated with a variety of histologically diverse B-cell lymphomas, each associated with specific viral-latency gene expression programs. Initial infection drives resting B-cells to differentiate via an atypical germinal centre reaction into memory B-cells, where the virus resides in a latent state. The mechanisms that underpin this process have yet to be fully elucidated. EBV expresses more than 40 microRNAs (miRNAs). The alternatively spliced BamHI A rightward transcripts (BARTs) are the template for two large miRNA clusters (BARTs A and B), that comprise the majority of all known EBV-miRNAs. Although BART-miRNAs are abundantly expressed in all latency programs, few BART-miRNA targets have been identified and their function is poorly understood. The early B-cell factor 1 (EBF1) was identified using bioinformaticss analysis as a novel target of EBV-miRNA BART11-5p, encoded by BART cluster B. EBF1 is an important B-cell transcription factor that regulates many B-cell specific genes including Pax5, BCR and CD40 and is critical for germinal centre formation. Using luciferase reporter assays and a series of BART-constructs, we confirmed silencing via the EBF1 3’ untranslated region (UTR) and identified the target site as 2137-2159 bp after the stop codon. Results were confirmed following transfection of a BART11-5p mimic, which was able to silence via the predicted target site. Our findings highlight a potential role of BART-miRNAs in the regulation of B-cell differentiation.
PMCID: PMC3755520  PMID: 23997984
EBV; microRNA; BamHI A rightward transcripts; early B-cell transcription factor; B-cell
2.  Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly expresses EBNA3A with conserved CD8+ T-cell epitopes 
Post-transplantation lymphoproliferative disorders (PTLD) arise in the immunosuppressed and are frequently Epstein-Barr virus (EBV) associated. The most common PTLD histological sub-type is diffuse large B-cell lymphoma (EBV+DLBCL-PTLD). Restoration of EBV-specific T-cell immunity can induce EBV+DLBCL-PTLD regression. The most frequent B-cell lymphoma in the immunocompetent is also DLBCL. ‘EBV-positive DLBCL of the elderly’ (EBV+DLBCL) is a rare but well-recognized DLBCL entity that occurs in the overtly immunocompetent, that has an adverse outcome relative to EBV-negative DLBCL. Unlike PTLD (which is classified as viral latency III), literature suggests EBV+DLBCL is typically latency II, i.e. expression is limited to the immuno-subdominant EBNA1, LMP1 and LMP2 EBV-proteins. If correct, this would be a major impediment for T-cell immunotherapeutic strategies. Unexpectedly we observed EBV+DLBCL-PTLD and EBV+DLBCL both shared features consistent with type III EBV-latency, including expression of the immuno-dominant EBNA3A protein. Extensive analysis showed frequent polymorphisms in EB-NA1 and LMP1 functionally defined CD8+ T-cell epitope encoding regions, whereas EBNA3A polymorphisms were very rare making this an attractive immunotherapy target. As with EBV+DLBCL-PTLD, the antigen presenting machinery within lymphomatous nodes was intact. EBV+DLBCL express EBNA3A suggesting it is amenable to immunotherapeutic strategies.
PMCID: PMC3301425  PMID: 22432076
Epstein-Barr virus; diffuse large B-cell lymphoma; EBNA3A; T-cell; epitope; immunotherapy; posttransplantation lymphoproliferative disorder
3.  Molecular mechanisms influencing NK cell development: implications for NK cell malignancies 
Natural Killer (NK) cells are important effector cells in both the innate and adaptive immune responses. Although they were identified almost 40 years ago, our understanding of how and where NK cells develop is rudimentary. In particular, we have only a limited understanding of the signaling pathways that need to be activated to cause NK cell commitment and maturation. Knowledge of this process is important as disruptions can lead to the development of highly aggressive NK cell malignancies. In this review, we discuss the known molecular mechanisms that trigger NK cell commitment, prompt them to mature and finally allow them to become functional killers. Known disruptions in this developmental process, and how they may contribute to malignancy, are also addressed.
PMCID: PMC3301417  PMID: 22432064
Animal; human; Natural Killer cell; transcription factors; cytokines; cell differentiation; lymphopoiesis; gene expression regulation; lymphoma

Results 1-3 (3)