scholarly journals Virally Induced Cellular MicroRNA miR-155 Plays a Key Role in B-Cell Immortalization by Epstein-Barr Virus

2010 ◽  
Vol 84 (22) ◽  
pp. 11670-11678 ◽  
Author(s):  
Sarah D. Linnstaedt ◽  
Eva Gottwein ◽  
Rebecca L. Skalsky ◽  
Micah A. Luftig ◽  
Bryan R. Cullen
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Epstein Barr Virus ◽  
B Cell Lymphoma ◽  
Selective Inhibition ◽  
B Cell Lymphomas ◽  
Cell Infection ◽  
Barr Virus ◽  
Epstein Barr

ABSTRACT Infection of resting primary human B cells by Epstein-Barr virus (EBV) results in their transformation into indefinitely proliferating lymphoblastoid cell lines (LCLs). LCL formation serves as a model for lymphomagenesis, and LCLs are phenotypically similar to EBV-positive diffuse large B-cell lymphomas (DLBCLs), which represent a common AIDS-associated malignancy. B-cell infection by EBV induces the expression of several cellular microRNAs (miRNAs), most notably miR-155, which is overexpressed in many tumors and can induce B-cell lymphomas when overexpressed in animals. Here, we demonstrate that miR-155 is the most highly expressed miRNA in LCLs and that the selective inhibition of miR-155 function specifically inhibits the growth of both LCLs and the DLBCL cell line IBL-1. Cells lacking miR-155 are inefficient in progressing through S phase and spontaneously undergo apoptosis. In contrast, three other B-cell lymphoma lines, including two EBV-positive Burkitt's lymphoma cell lines, grew normally in the absence of miR-155 function. These data identify the induction of cellular miR-155 expression by EBV as critical for the growth of both laboratory-generated LCLs and naturally occurring DLBCLs and suggest that targeted inhibition of miR-155 function could represent a novel approach to the treatment of DLBCL in vivo.

scholarly journals Epstein Barr virus-positive B-cell lymphoma is highly vulnerable to MDM2 inhibitors in vivo

2021 ◽  
Author(s):  
Xiaoshan Zhang ◽  
Ran Zhang ◽  
Chenghui Ren ◽  
Yi Xu ◽  
Shuhong Wu ◽  
...  
Keyword(s):  
B Cell ◽  
Epstein Barr Virus ◽  
Cell Lymphoma ◽  
Tumor Regression ◽  
B Cell Lymphoma ◽  
B Cell Lymphomas ◽  
T Cell Therapy ◽  
Barr Virus ◽  
Epstein Barr

Epstein-Barr virus (EBV)-positive B-cell lymphomas are common in immunocompromised patients and remain an unmet medical need. Here we report that MDM2 inhibitors (MDM2i) navtemadlin and idasanutlin have potent in vivo activity in EBV+ B-cell lymphoma established in immunocompromised mice. Tumor regression was observed in all 5 EBV+ xenograft-associated B-cell lymphomas treated with navtemadlin or idasanutlin. Molecular characterization showed that treatment with MDM2i resulted in activation of p53 pathways and downregulation of cell cycle effectors in human lymphoma cell lines that either were EBV+ or had undetectable expression of BCL6, a transcriptional inhibitor of the TP53 gene. Moreover, treatment with navtemadlin resulted in tumor regression and prevented systemic dissemination of EBV+ lymphoma derived from 2 juvenile patients with posttransplant lymphoproliferative diseases, including one whose tumor was resistant to virus-specific T-cell therapy. These results provide proof-of-concept for targeted therapy of EBV+ lymphoma with MDM2i and the feasibility of using EBV infection or loss of BCL6 expression to identify responders to MDM2i.

scholarly journals Establishment of two Epstein-Barr virus negative Burkitt cell lines from a patient with AIDS and B-cell lymphoma

Blood ◽  
1988 ◽  
Vol 72 (4) ◽  
pp. 1255-1260 ◽  
Author(s):  
A Ganser ◽  
C Carlo-Stella ◽  
CR Bartram ◽  
T Boehm ◽  
G Heil ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Epstein Barr Virus ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
Immunoglobulin Gene ◽  
Barr Virus ◽  
Epstein Barr ◽  
Immunodeficiency Syndrome

Abstract To analyze the pathogenesis of B-cell lymphomas in patients with acquired immunodeficiency syndrome (AIDS), we studied two cell lines, Es I and Es III, established from one such lymphoma for the presence of sequences of the Epstein-Barr virus (EBV) and the human immunodeficiency virus [HIV; lymphadenopathy-associated virus (LAV/HTLV- III)] as well as for the presence of cytogenetic abnormalities and monoclonal rearrangements of immunoglobulin and T-cell receptor genes. Both cell lines expressed the same IgM, kappa phenotype as the original lymphoma. The karyotype of Es I was 46, XY, t(8;14), 2 p+, inv (6p), 17p-, and the cells of Es III had an additional i(7q). Immunoglobulin gene studies demonstrated the identical monoclonal rearrangements in both cell lines. Neither EBV nor HIV sequences were detectable in the malignant B cells at the genomic level, leading to the conclusion that mechanisms other than transformation by EBV or HIV may have contributed to the B-cell lymphoma in this patient and possibly also to the generally increased frequency in patients with AIDS.

Transformation of Small B-Cell Lymphoma Into Large Cell CD30+, CD4+, Epstein-Barr Virus–Negative Lymphoma

2014 ◽  
Vol 138 (8) ◽  
pp. 1101-1105 ◽  
Author(s):  
Aaron C. Shaver ◽  
Ly Ma ◽  
Cindy Vnencak-Jones ◽  
Roland S. Schwarting ◽  
Kristina J. Fasig ◽  
...  
Keyword(s):  
B Cell ◽  
Epstein Barr Virus ◽  
Cell Lymphoma ◽  
Relevant Literature ◽  
B Cell Lymphoma ◽  
Low Grade ◽  
B Cell Lymphomas ◽  
Barr Virus ◽  
Wide Range ◽  
Epstein Barr

We report here 2 separate cases in which patients with known low-grade B-cell lymphomas presented with transformed lesions that were CD30+, CD4+, Epstein-Barr virus negative, and negative or focally weak for a wide range of B-cell, T-cell, and histiocytic/dendritic cell markers. In each case the transformed lymphoma possessed an identical pattern of immunoglobulin heavy chain and/or BCL2 rearrangement to the corresponding original low-grade B-cell lymphoma, confirming their identity as transformed B-cell lymphoma. A review of the relevant literature reveals that, to our knowledge, no transformed B-cell lymphomas with this immunophenotype have been previously reported, which creates the opportunity for potential errors of diagnosis. These cases highlight the importance of correlation with the patient's history and with molecular genetic results in rendering an accurate diagnosis.

scholarly journals Epstein-Barr Virus Infection of Cell Lines Derived from Diffuse Large B-Cell Lymphomas Alters MicroRNA Loading of the Ago2 Complex

2018 ◽  
Vol 93 (3) ◽  
Author(s):  
Hiresh Ayoubian ◽  
Nicole Ludwig ◽  
Tobias Fehlmann ◽  
Jennifer Menegatti ◽  
Laura Gröger ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Epstein Barr Virus ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Northern Blotting ◽  
Barr Virus ◽  
Large B Cell Lymphoma ◽  
Epstein Barr ◽  
Large B Cell

ABSTRACT Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoid tumor which is occasionally Epstein-Barr virus (EBV) positive and is further subtyped as activated B-cell DLBCL (ABC-DLBCL) and germinal center B-cell DLBCL (GCB-DLBCL), which has implications for prognosis and treatment. We performed Ago2 RNA immunoprecipitation followed by high-throughput RNA sequencing (Ago2-RIP-seq) to capture functionally active microRNAs (miRNAs) in EBV-negative ABC-DLBCL and GCB-DLBCL cell lines and their EBV-infected counterparts. In parallel, total miRNA profiles of these cells were determined to capture the cellular miRNA profile for comparison with the functionally active profile. Selected miRNAs with differential abundances were validated using real-time quantitative PCR (RT-qPCR) and Northern blotting. We found 6 miRNAs with differential abundances (2 upregulated and 4 downregulated miRNAs) between EBV-negative and -positive ABC-DLBCL cells and 12 miRNAs with differential abundances (3 upregulated and 9 downregulated miRNAs) between EBV-negative and -positive GCB-DLBCL cells. Eight and twelve miRNAs were confirmed using RT-qPCR in ABC-DLBCL and GCB-DLBCL cells, respectively. Selected miRNAs were analyzed in additional type I/II versus type III EBV latency DLBCL cell lines. Furthermore, upregulation of miR-221-3p and downregulation of let7c-5p in ABC-DLBCL cells and upregulation of miR-363-3p and downregulation of miR-423-5p in GCB-DLBCL cells were verified using RIP-Northern blotting. Our comprehensive sequence analysis of the DLBCL miRNA profiles identified sets of deregulated miRNAs by Ago2-RIP-seq. Our Ago2-IP-seq miRNA profile could be considered an important data set for the detection of deregulated functionally active miRNAs in DLBCLs and could possibly lead to the identification of miRNAs as biomarkers for the classification of DLBCLs or even as targets for personalized targeted treatment. IMPORTANCE Diffuse large B-cell lymphoma (DLBCL) is a highly aggressive tumor of lymphoid origin which is occasionally Epstein-Barr virus (EBV) positive. MicroRNAs are found in most multicellular organisms and even in viruses such as EBV. They regulate the synthesis of proteins by binding to their cognate mRNA. MicroRNAs are tethered to their target mRNAs by “Argonaute” proteins. Here we compared the overall miRNA content of the Ago2 complex by differential loading to the overall content of miRNAs in two DLBCL cell lines and their EBV-converted counterparts. In all cell lines, the Ago2 load was different from the overall expression of miRNAs. In addition, the loading of the Ago2 complex was changed upon infection with EBV. This indicates that the virus not only changes the overall content of miRNAs but also influences the expression of proteins by affecting the Ago complexes.

scholarly journals In Vivo Function of a Gammaherpesvirus Virion Glycoprotein: Influence on B-Cell Infection and Mononucleosis

2004 ◽  
Vol 78 (19) ◽  
pp. 10449-10459 ◽  
Author(s):  
James P. Stewart ◽  
Ondine J. Silvia ◽  
Isobel M. D. Atkin ◽  
David J. Hughes ◽  
Bahram Ebrahimi ◽  
...  
Keyword(s):  
B Cell ◽  
Epstein Barr Virus ◽  
Wild Type Virus ◽  
Target Cells ◽  
Cell Infection ◽  
Barr Virus ◽  
Extracellular Virus ◽  
Epstein Barr

ABSTRACT The human gammaherpesviruses Epstein-Barr virus and Kaposi Sarcoma-associated herpesvirus both contain a glycoprotein (gp350/220 and K8.1, respectively) that mediates binding to target cells and has been studied in great detail in vitro. However, there is no direct information on the role that these glycoproteins play in pathogenesis in vivo. Infection of mice by murid herpesvirus 4 strain 68 (MHV-68) is an established animal model for gammaherpesvirus pathogenesis and expresses an analogous glycoprotein, gp150. To elucidate the in vivo function of gp150, a recombinant MHV-68 deficient in gp150 production was generated (vgp150Δ). The productive viral replication in vitro and in vivo was largely unaffected by mutation of gp150, aside from a partial defect in the release of extracellular virus. Likewise, B-cell latency was established. However, the transient mononucleosis and spike in latently infected cells associated with the spread of MHV-68 to the spleen was significantly reduced in vgp150Δ-infected mice. A soluble, recombinant gp150 was found to bind specifically to B cells but not to epithelial cells in culture. In addition, gp150-deficient MHV-68 derived from mouse lungs bound less well to spleen cells than wild-type virus. Thus, gp150 is highly similar in function in vitro to the Epstein-Barr virus gp350/220. These results suggest a role for these analogous proteins in mononucleosis and have implications for their use as vaccine antigens.

Imatinib mesylate reduces rituximab-induced tumor-growth inhibition in vivo on Epstein???Barr virus-associated human B-cell lymphoma

2007 ◽  
Vol 18 (9) ◽  
pp. 1029-1037 ◽  
Author(s):  
Fariba N??mati ◽  
Claire Mathiot ◽  
Isabelle Grandjean ◽  
Olivier Lantz ◽  
Vincent Bordier ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Tumor Growth Inhibition ◽  
Barr Virus ◽  
Epstein Barr ◽  
Human B Cell

scholarly journals Induction of Lytic Epstein-Barr Virus (EBV) Infection by Synergistic Action of Rituximab and Dexamethasone Renders EBV-Positive Lymphoma Cells More Susceptible to Ganciclovir Cytotoxicity In Vitro and In Vivo

2005 ◽  
Vol 79 (9) ◽  
pp. 5875-5879 ◽  
Author(s):  
Masanori Daibata ◽  
Kentaro Bandobashi ◽  
Masayuki Kuroda ◽  
Shosuke Imai ◽  
Isao Miyoshi ◽  
...  
Keyword(s):  
B Cell ◽  
Epstein Barr Virus ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphoma Cells ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

ABSTRACT The purposeful induction of the lytic form of Epstein-Barr virus (EBV) infection combined with ganciclovir (GCV) treatment has been advocated as a novel strategy for EBV-positive B-cell lymphoma. We demonstrated that rituximab had a synergistic effect with dexamethasone on induction of the lytic EBV infection in CD20-positive lymphoma cells. Addition of GCV to the dexamethasone/rituximab-treated cells was more effective than dexamethasone/rituximab alone in killing EBV-positive lymphoma cells in vitro and in lymphoma-bearing nude mice but not in EBV-negative cells. These data suggest that induction of the lytic EBV infection with dexamethasone/rituximab in combination with GCV could be a potential virally targeted therapy for EBV-associated B-cell lymphoma.

scholarly journals Cataloguing over-expressed genes in Epstein Barr Virus immortalized lymphoblastoid cell lines through consensus analysis of PacBio transcriptomes corroborates hypomethylation of chromosome 1

2017 ◽  
Author(s):  
Sandeep Chakraborty
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Epstein Barr Virus ◽  
B Cell Lymphoma ◽  
Peripheral Blood Lymphocytes ◽  
Chromosome 1 ◽  
Lymphoblastoid Cell Lines ◽  
Consensus Analysis ◽  
Barr Virus ◽  
Epstein Barr

AbstractThe ability of Epstein Barr Virus (EBV) to transform resting cell B-cells into immortalized lymphoblastoid cell lines (LCL) provides a continuous source of peripheral blood lymphocytes that are used to model conditions in which these lymphocytes play a key role. Here, the PacBio generated transcriptome of three LCLs from a parent-daughter trio (SRAid:SRP036136) provided by a previous study [1] were analyzed using a kmer-based version of YeATS (KEATS). The set of over-expressed genes in these cell lines were determined based on a comparison with the PacBio transcriptome of twenty tissues provided by another study (hOPTRS) [2]. MIR155 long non-coding RNA (MIR155HG), Fc fragment of IgE receptor II (FCER2), T-cell leukemia/lymphoma 1A (TCL1A), and germinal center associated signaling and motility (GCSAM) were genes having the highest expression counts in the three LCLs with no expression in hOPTRS. Other over-expressed genes, having low expression in hOPTRS, were membrane spanning 4-domains A1 (MS4A1) and ribosomal protein S2 pseudogene 55 (RPS2P55). While some of these genes are known to be over-expressed in LCLs, this study provides a comprehensive cataloguing of such genes. A recent work involving a patient with EBV-positive large B-cell lymphoma was ‘unusually lacking various B-cell markers’, but over-expressing CD30 [3] - a gene ranked 79 among uniquely expressed genes here. Hypomethylation of chromosome 1 observed in EBV immortalized LCLs [4, 5] is also corroborated here by mapping the genes to chromosomes. Extending previous work identifying un-annotated genes [6], 80 genes were identified which are expressed in the three LCLs, not in hOPTRS, and missing in the GENCODE, RefSeq and RefSeqGene databases. KEATS introduces a method of determining expression counts based on a partitioning of the known annotated genes, has runtimes of a few hours on a personal workstation and provides detailed reports enabling proper debugging.

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