Dataset Information

Thermodynamic and structural characterization of an EBV infected B-cell lymphoma transcriptome.

ABSTRACT: Epstein-Barr virus (EBV) is a widely prevalent human herpes virus infecting over 95% of all adults and is associated with a variety of B-cell cancers and induction of multiple sclerosis. EBV accomplishes this in part by expression of coding and noncoding RNAs and alteration of the host cell transcriptome. To better understand the structures which are forming in the viral and host transcriptomes of infected cells, the RNA structure probing technique Structure-seq2 was applied to the BJAB-B1 cell line (an EBV infected B-cell lymphoma). This resulted in reactivity profiles and secondary structural analyses for over 10000 human mRNAs and lncRNAs, along with 19 lytic and latent EBV transcripts. We report in-depth structural analyses for the human MYC mRNA and the human lncRNA CYTOR. Additionally, we provide a new model for the EBV noncoding RNA EBER2 and provide the first reported model for the EBV tandem terminal repeat RNA. In-depth thermodynamic and structural analyses were carried out with the motif discovery tool ScanFold and RNAfold prediction tool; subsequent covariation analyses were performed on resulting models finding various levels of support. ScanFold results for all analyzed transcripts are made available for viewing and download on the user-friendly RNAStructuromeDB.

SUBMITTER: O'Leary CA

PROVIDER: S-EPMC9585548 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Thermodynamic and structural characterization of an EBV infected B-cell lymphoma transcriptome.

O'Leary Collin A CA Van Tompkins S S Rouse Warren B WB Nam Gijong G Moss Walter N WN

NAR genomics and bioinformatics 20221021 4

Epstein-Barr virus (EBV) is a widely prevalent human herpes virus infecting over 95% of all adults and is associated with a variety of B-cell cancers and induction of multiple sclerosis. EBV accomplishes this in part by expression of coding and noncoding RNAs and alteration of the host cell transcriptome. To better understand the structures which are forming in the viral and host transcriptomes of infected cells, the RNA structure probing technique Structure-seq2 was applied to the BJAB-B1 cell ...[more]

PMID: 36285286

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Project description:Endemic Burkitt lymphoma (eBL) is the most common pediatric cancer in malaria-endemic equatorial Africa and nearly always contains Epstein-Barr virus (EBV), unlike sporadic Burkitt lymphoma (sBL) that occurs with a lower incidence in developed countries. Given these differences and the variable clinical presentation and outcomes, we sought to further understand pathogenesis by investigating transcriptomes using RNA sequencing (RNAseq) from multiple primary eBL tumors compared with sBL tumors. Within eBL tumors, minimal expression differences were found based on: anatomical presentation site, in-hospital survival rates, and EBV genome type, suggesting that eBL tumors are homogeneous without marked subtypes. The outstanding difference detected using surrogate variable analysis was the significantly decreased expression of key genes in the immunoproteasome complex (PSMB9/β1i, PSMB10/β2i, PSMB8/β5i, and PSME2/PA28β) in eBL tumors carrying type 2 EBV compared with type 1 EBV. Second, in comparison with previously published pediatric sBL specimens, the majority of the expression and pathway differences was related to the PTEN/PI3K/mTOR signaling pathway and was correlated most strongly with EBV status rather than geographic designation. Third, common mutations were observed significantly less frequently in eBL tumors harboring EBV type 1, with mutation frequencies similar between tumors with EBV type 2 and without EBV. In addition to the previously reported genes, a set of new genes mutated in BL, including TFAP4, MSH6, PRRC2C, BCL7A, FOXO1, PLCG2, PRKDC, RAD50, and RPRD2, were identified. Overall, these data establish that EBV, particularly EBV type 1, supports BL oncogenesis, alleviating the need for certain driver mutations in the human genome.ImplicationsGenomic and mutational analyses of Burkitt lymphoma tumors identify key differences based on viral content and clinical outcomes suggesting new avenues for the development of prognostic molecular biomarkers and therapeutic interventions.

Project description:BACKGROUNDAdoptive transfer of donor-derived EBV-specific cytotoxic T-lymphocytes (EBV-CTLs) can eradicate EBV-associated lymphomas (EBV-PTLD) after transplantation of hematopoietic cell (HCT) or solid organ (SOT) but is unavailable for most patients.METHODSWe developed a third-party, allogeneic, off-the-shelf bank of 330 GMP-grade EBV-CTL lines from specifically consented healthy HCT donors. We treated 46 recipients of HCT (n = 33) or SOT (n = 13) with established EBV-PTLD, who had failed rituximab therapy, with third-party EBV-CTLs. Treatment cycles consisted of 3 weekly infusions of EBV-CTLs and 3 weeks of observation.RESULTSEBV-CTLs did not induce significant toxicities. One patient developed grade I skin graft-versus-host disease. Complete remission (CR) or sustained partial remission (PR) was achieved in 68% of HCT recipients and 54% of SOT recipients. For patients who achieved CR/PR or stable disease after cycle 1, one year overall survival was 88.9% and 81.8%, respectively. In addition, 3 of 5 recipients with POD after a first cycle who received EBV-CTLs from a different donor achieved CR or durable PR (60%) and survived longer than 1 year. Maximal responses were achieved after a median of 2 cycles.CONCLUSIONThird-party EBV-CTLs of defined HLA restriction provide safe, immediately accessible treatment for EBV-PTLD. Secondary treatment with EBV-CTLs restricted by a different HLA allele (switch therapy) can also induce remissions if initial EBV-CTLs are ineffective. These results suggest a promising potential therapy for patients with rituximab-refractory EBV-associated lymphoma after transplantation.TRIAL REGISTRATIONPhase II protocols (NCT01498484 and NCT00002663) were approved by the Institutional Review Board at Memorial Sloan Kettering Cancer Center, the FDA, and the National Marrow Donor Program.FUNDINGThis work was supported by NIH grants CA23766 and R21CA162002, the Aubrey Fund, the Claire Tow Foundation, the Major Family Foundation, the Max Cure Foundation, the Richard "Rick" J. Eisemann Pediatric Research Fund, the Banbury Foundation, the Edith Robertson Foundation, and the Larry Smead Foundation. Atara Biotherapeutics licensed the bank of third-party EBV-CTLs from Memorial Sloan Kettering Cancer Center in June 2015.

Dataset Information

Thermodynamic and structural characterization of an EBV infected B-cell lymphoma transcriptome.

Publications

Thermodynamic and structural characterization of an EBV infected B-cell lymphoma transcriptome.

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