104 results on '"Vockerodt, M."'
Search Results
2. Correction: S1PR1 drives a feedforward signalling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells
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Vrzalikova, K, Ibrahim, M, Vockerodt, M, Perry, T, Margielewska, S, Lupino, L, Nagy, E, Soilleux, E, Liebelt, D, Hollows, R, Last, A, Reynolds, G, Abdullah, M, Curley, H, Care, M, Krappmann, D, Tooze, R, Allegood, J, Spiegel, S, Wei, W, Woodman, C B J, and Murray, P G
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- 2019
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3. The H3K27me3 demethylase, KDM6B, is induced by Epstein–Barr virus and over-expressed in Hodgkin's Lymphoma
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Anderton, J A, Bose, S, Vockerodt, M, Vrzalikova, K, Wei, W, Kuo, M, Helin, K, Christensen, J, Rowe, M, Murray, P G, and Woodman, C B
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- 2011
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4. STAT3 is essential for Hodgkin lymphoma cell proliferation and is a target of tyrphostin AG17 which confers sensitization for apoptosis
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Holtick, U, Vockerodt, M, Pinkert, D, Schoof, N, Stürzenhofecker, B, Kussebi, N, Lauber, K, Wesselborg, S, Löffler, D, Horn, F, Trümper, L, and Kube, D
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- 2005
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5. Simultaneous analysis of interleukin-10 gene microsatellites and single-nucleotide polymorphisms in parallel with tumour necrosis factor and interferon-gamma short tandem repeats by fluorescence-based polymerase chain reaction
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Kube, D, Mörmann, M, Tomiuk, J, Rieth, H, Hua, T D, Kremsner, P G, and Vockerodt, M
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- 2003
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6. Epstein–Barr virus latent membrane protein-1 activates CD25 expression in lymphoma cells involving the NFκB pathway
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Vockerodt, M, Tesch, H, and Kube, D
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- 2001
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7. Immunomagnetic enrichment of CD138 positive cells from weakly infiltrated myeloma patients samples enables the determination of the tumor clone specific IgH rearrangement
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Draube, A., Pfister, R., Vockerodt, M., Schuster, S., Kube, D., Diehl, V., and Tesch, H.
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- 2001
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8. The Epstein–Barr virus oncoprotein, latent membrane protein-1, reprograms germinal centre B cells towards a Hodgkinʼs Reed–Sternberg-like phenotype#
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Vockerodt, M, Morgan, S L, Kuo, M, Wei, W, Chukwuma, M B, Arrand, J R, Kube, D, Gordon, J, Young, L S, Woodman, C B, and Murray, P G
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- 2008
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9. Inhibition of cell proliferation by tyrphostins - Mode of action in Hodgkinʼs lymphoma cells: P912
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Kussebi, N., Stürzenhofecker, B., Choi, E.-M., Vockerodt, M., Trümper, L., and Kube, D.
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- 2003
10. Epstein-Barr virus LMP1 associated cytokine expression in lymphoma cell lines: 726
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Kube, D. and Vockerodt, M.
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- 2002
11. C-FLIP is constitutively expressed by Hodgkin and Reed-Sternberg cells: 696
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Thomas, R. K., Kallenborn, A., Wickenhauser, C., Schultze, J. L., Draube, A., Vockerodt, M., Re, D., Diehl, V., and Wolf, J.
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- 2002
12. Detection of a Hodgkin/Reed-Sternberg cell specific immunoglobulin gene rearrangement in the serum DNA of a patient with Hodgkin's disease
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Kornacker, M., Jox, A., Vockerodt, M., Tesch, H., Bohlen, H., Diehl, V., and Wolf, J.
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- 1999
13. S1PR1 drives a feed forward signalling loop to regulate BATF3 and the transcriptional programme of hodgkin lymphoma cells
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Vrzalikova, K., Ibrahim, M., Vockerodt, M., Perry, T., Margielewska, S., Lupino, L., Nagy, E., Soilleux, E., Liebelt, D., Hollows, R., Last, A., Reynolds, G., Abdullah, M., Curley, H., Care, M., Krappmann, D., Tooze, R., Allegood, J., Spiegel, S., Wei, W., Woodman, C.B.J., and Murray, P.G.
- Abstract
The Hodgkin/Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (HL) are characterised by the aberrant activation of multiple signalling pathways. Here we show that a subset of HL displays altered expression of sphingosine-1-phosphate (S1P) receptors (S1PR). S1P activates phosphatidylinositide 3-kinase (PI3-K) in these cells that is mediated by the increased expression of S1PR1 and the decreased expression of S1PR2. We also showed that genes regulated by PI3-K signalling pathway in HL cell lines significantly overlap with the transcriptional programme of primary HRS cells. Genes up-regulated by the PI3-K pathway included the basic leucine zipper transcription factor, ATF-like 3 (BATF3), which is normally associated with the development of dendritic cells. Immunohistochemistry confirmed that BATF3 was expressed in HRS cells of most HL cases. In contrast, in normal lymphoid tissues, BATF3 expression was confined to a small fraction of CD30-positive immunoblasts. Knockdown of BATF3 in HL cell lines revealed that BATF3 contributed to the transcriptional programme of primary HRS cells, including the upregulation of S1PR1. Our data suggest that disruption of this potentially oncogenic feed-forward S1P signalling loop could provide novel therapeutic opportunities for patients with HL.Leukemia accepted article preview online, 07 September 2017. doi:10.1038/leu.2017.275.
- Published
- 2017
14. S1PR1 drives a feedforward signaling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells
- Author
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Vrzalikova, K., Ibrahim, M., Vockerodt, M., Perry, T., Margielewska, S., Lupino, L., Nagy, E., Soilleux, E., Liebelt, D., Hollows, R., Last, A., Reynolds, G., Abdullah, M., Curley, H., Care, M., Krappmann, D., Tooze, R., Allegood, J., Spiegel, S., Wei, W., Woodman, C. B. J., Murray, P. G., Vrzalikova, K., Ibrahim, M., Vockerodt, M., Perry, T., Margielewska, S., Lupino, L., Nagy, E., Soilleux, E., Liebelt, D., Hollows, R., Last, A., Reynolds, G., Abdullah, M., Curley, H., Care, M., Krappmann, D., Tooze, R., Allegood, J., Spiegel, S., Wei, W., Woodman, C. B. J., and Murray, P. G.
- Abstract
The Hodgkin/Reed–Sternberg cells of classical Hodgkin lymphoma (HL) are characterised by the aberrant activation of multiple signalling pathways. Here we show that a subset of HL displays altered expression of sphingosine-1-phosphate (S1P) receptors (S1PR)s. S1P activates phosphatidylinositide 3-kinase (PI3-K) in these cells that is mediated by the increased expression of S1PR1 and the decreased expression of S1PR2. We also showed that genes regulated by the PI3-K signalling pathway in HL cell lines significantly overlap with the transcriptional programme of primary HRS cells. Genes upregulated by the PI3-K pathway included the basic leucine zipper transcription factor, ATF-like 3 (BATF3), which is normally associated with the development of dendritic cells. Immunohistochemistry confirmed that BATF3 was expressed in HRS cells of most HL cases. In contrast, in normal lymphoid tissues, BATF3 expression was confined to a small fraction of CD30-positive immunoblasts. Knockdown of BATF3 in HL cell lines revealed that BATF3 contributed to the transcriptional programme of primary HRS cells, including the upregulation of S1PR1. Our data suggest that disruption of this potentially oncogenic feedforward S1P signalling loop could provide novel therapeutic opportunities for patients with HL.
- Published
- 2017
15. S1PR1 drives a feedforward signalling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells
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Vrzalikova, K, primary, Ibrahim, M, additional, Vockerodt, M, additional, Perry, T, additional, Margielewska, S, additional, Lupino, L, additional, Nagy, E, additional, Soilleux, E, additional, Liebelt, D, additional, Hollows, R, additional, Last, A, additional, Reynolds, G, additional, Abdullah, M, additional, Curley, H, additional, Care, M, additional, Krappmann, D, additional, Tooze, R, additional, Allegood, J, additional, Spiegel, S, additional, Wei, W, additional, Woodman, C B J, additional, and Murray, P G, additional
- Published
- 2017
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16. Stable nontumorigenic phenotype of somatic cell hybrids between malignant Burkitt's lymphoma cells and autologous EBV-immortalized B cells despite induction of chromosomal breakage and loss
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Jox A, Taquia E, Vockerodt M, Draube A, Michael Pawlita, Möller P, Bullerdiek J, Diehl V, and Wolf J
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Chromosome Aberrations ,B-Lymphocytes ,Herpesvirus 4, Human ,Mice, Nude ,Hybrid Cells ,Lymphocyte Activation ,Burkitt Lymphoma ,Cell Line ,Cell Fusion ,Viral Matrix Proteins ,Mice ,Phenotype ,Animals ,Humans ,Female - Abstract
Fusion of the highly tumorigenic Burkitt's lymphoma (BL) cell line BL60-P7 with the nontumorigenic autologous EBV-immortalized lymphoblastoid cell line (LCL) IARC 277 results in suppression of the tumorigenic phenotype of the parental cell line BL60-P7 after s.c. inoculation into T cell-deficient nude mice. We analyzed whether, after long-term cultivation of these lymphoma hybrid cells, expression of tumorigenicity could be observed and correlated to the loss of particular chromosomes or chromosomal fragments, akin to numerous nonlymphoid hybrid cell models described previously. Two years after fusion, in vitro proliferation of some BL x LCL hybrid cells accelerated, and they partially lost LCL-typical aggregation. However, no major changes in the expression pattern of B cell-associated surface antigens and the EBV latent membrane protein LMP 1 were observed. Cytogenetic evaluation of these cells revealed spontaneous loss of chromosomes. Karyotyping of long-term cultivated hybrid cells demonstrated the occurrence of disomy for each chromosome in at least one metaphase analyzed. Therefore, if suppression of tumorigenicity in these hybrid cells would have been the result of the presence of a single LCL-derived chromosome, there should have been a high probability of its loss, leading to tumorigenic segregants. Surprisingly, the tumorigenic phenotype remained suppressed in nude mice. To induce chromosomal breakage and maldistribution, in addition to spontaneous chromosomal loss, the hybrid cell lines were irradiated at various doses. Again, none of the hybrid cell clones treated in this manner became tumorigenic in nude mice. Immunohistological analysis of the regressing hybrid cell tumors revealed that the hybrid cells had retained their LCL-like differentiation phenotype in vivo. In addition, infiltration with mononuclear cells of murine origin was observed in these regressing hybrid grafts. We conclude that suppression of the tumorigenic Burkitt's lymphoma phenotype in these hybrid cells cannot be attributed to a function encoded by a distinct chromosome or chromosomal fragment. Rather, the unexpected stable nontumorigenic phenotype reflects a LCL-specific activated B-cell phenotype of these hybrids, most probably induced by the expression of numerous copies of episomal latent EBV proteins.
- Published
- 1998
17. Detection of clonal Hodgkin and Reed-Sternberg cells with identical somatically mutated and rearranged VH genes in different biopsies in relapsed Hodgkin's disease
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Vockerodt M, Soares M, Kanzler H, Ralf Küppers, Kube D, Ml, Hansmann, Diehl V, and Tesch H
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Adult ,Neoplasm, Residual ,Biopsy ,Immunology ,Molecular Sequence Data ,Gene Rearrangement, B-Lymphocyte, Heavy Chain ,Immunoglobulin Variable Region ,Biochemistry ,Polymerase Chain Reaction ,Sensitivity and Specificity ,Recurrence ,Sequence Homology, Nucleic Acid ,Humans ,Amino Acid Sequence ,Reed-Sternberg Cells ,B-Lymphocytes ,Base Sequence ,Genes, Immunoglobulin ,Hematopoietic Stem Cell Transplantation ,Cell Biology ,Hematology ,Hodgkin Disease ,Clone Cells ,Female ,Lymph Nodes ,Immunoglobulin Heavy Chains ,Sequence Alignment ,Spleen - Abstract
Hodgkin’s disease (HD) represents a malignant lymphoma in which the putative malignant Hodgkin and Reed-Sternberg (H-RS) cells are rare and surrounded by abundant reactive cells. Single-cell analyses showed that H-RS cells regularly bear clonal Ig gene rearrangements. However, there is little information on the clinical evolution of HD in a given patient. In this study, we used the single-cell polymerase chain reaction (PCR) to identify H-RS cells with clonal Ig gene rearrangements in biopsy specimens of patients with relapsed HD. The obtained clonal variable region heavy-chain (VH) gene rearrangements were used to construct tumor-clone-specific oligonucleotides spanning the complementarity determining region (CDR) III and somatically mutated areas in the rearranged VHgene. A number of biopsies were obtained during a period of 3 years from two HD patients. H-RS cells with identical VHrearrangements were detected in two separate infiltrated lymph nodes from one patient with nodular sclerosis HD. In a second patient with mixed cellularity HD subtype, clonal VH rearrangements with identical sequences were detected in infiltrated spleen and two lymph node biopsies. Despite the high sensitivity of the PCR method used (one clonal cell in 105 mononuclear cells), residual H-RS cells were not found in peripheral blood, leukapheresis material, purified CD34+ stem cells or bone marrow. The results show that different specimens from relapsed patients suffering from classical HD carry the same clonotypic IgH rearrangements with identical somatic mutations, demonstrating the persistence and the dissemination of a clonal tumor cell population. Thus, PCR assays with CDRIII-specific probes derived from clonal H-RS cells are of clinical importance in monitoring the dissemination of HD and tumor progression and could be useful for analysis of minimal residual disease after autologous stem cell transplantation. © 1998 by The American Society of Hematology.
- Published
- 1998
18. 558 Epstein Barr virus latent membrane protein 1 in Hodgkin lymphoma
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Lee, L.K., primary, Chandran, P.A., additional, Vockerodt, M., additional, Woodman, C.B., additional, Murray, P.G., additional, and Cheah, S.H., additional
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- 2010
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19. 417 A c-Myc induced gene expression signature in human germinal center B cells predicts subtypes of aggressive non-Hodgkin Lymphoma
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Schrader, A., primary, Bentink, S., additional, Spang, R., additional, Lenze, D., additional, Hummel, M., additional, Kuo, M., additional, Murray, P., additional, Trümper, L., additional, Kube, D., additional, and Vockerodt, M., additional
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- 2010
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20. Dissecting the molecular pathogenisis of Burkitt lymphoma
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Kube, D, primary, Matulewicz, K, additional, Schrader, A, additional, Bentink, S, additional, Spang, R, additional, Murray, P, additional, Trümper, L, additional, and Vockerodt, M, additional
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- 2009
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21. STAT3 is constitutively activated in Hodgkin cell lines
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Kube, D., Holtick, U., Vockerodt, M., Ahmadi, T., Haier, B., Behrmann, Iris, Heinrich, P. C., Diehl, V., Tesch, H., Kube, D., Holtick, U., Vockerodt, M., Ahmadi, T., Haier, B., Behrmann, Iris, Heinrich, P. C., Diehl, V., and Tesch, H.
- Abstract
Hodgkin disease (HD) represents a malignant lymphoma in which the putative malignant Hodgkin and Reed-Sternberg cells are rare and surrounded by abundant reactive nonmalignant cells. It has been suggested that cytokines such as interleukin-6 (IL-6) are involved in the pathogenesis of the disease. The expression of the IL-6 receptor (IL-6R) complex and its link to the activation of signal transducers and activators of transcription (STAT) molecules in HD cell lines was investigated. Gel retardation and Western blot analyses revealed a high level of constitutively activated STAT3 in 5 of 7 HD cell lines, which could not be detected in Burkitt lymphoma cell lines. Different levels of IL-6R protein were measured in various HD cell lines: L428 and Dev cells were characterized by very low levels of gp80 and gp130, on KMH2 cells only gp130 but no gp80 was detected, whereas L540, L591, HDLM2, and L1236 were positive for both gp80 and gp130, suggesting a possible autocrine stimulation of STAT3. However, a further increase in STAT3 activation on IL-6 or IL-6/soluble IL-6R stimulation was not observed. Neutralizing monoclonal antibodies against IL-6, gp80, gp130, or both receptor subunits did not affect the proliferation or the constitutive activation of STAT molecules in HD cell lines. However, the tyrosine kinase inhibitor AG490 blocked the constitutive activation of STAT3 and inhibited spontaneous growth of HD tumor cells. The evidence suggests abnormal STAT signaling and growth regulation in Hodgkin cell lines. (Blood. 2001;98:762-770)
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- 2001
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22. Gli1 expression in rhabdomyosarcoma cells
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Vockerodt, M, primary, Wilting, J, additional, and Schweigerer, L, additional
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- 2004
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23. Expression of Epstein-Barr Virus Nuclear Antigen 1 Is Associated with Enhanced Expression of CD25 in the Hodgkin Cell Line L428
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Kube, D., primary, Vockerodt, M., additional, Weber, O., additional, Hell, K., additional, Wolf, J., additional, Haier, B., additional, Grässer, F. A., additional, Müller-Lantzsch, N., additional, Kieff, E., additional, Diehl, V., additional, and Tesch, H., additional
- Published
- 1999
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24. Correction: S1PR1 drives a feedforward signalling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells
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Vrzalikova, K, Ibrahim, M, Vockerodt, M, Perry, T, Margielewska, S, Lupino, L, Nagy, E, Soilleux, E, Liebelt, D, Hollows, R, Last, A, Reynolds, G, Abdullah, M, Curley, H, Care, M, Krappmann, D, Tooze, R, Allegood, J, Spiegel, S, Wei, W, Woodman, CBJ, and Murray, PG
- Subjects
3201 Cardiovascular Medicine and Haematology ,32 Biomedical and Clinical Sciences ,3211 Oncology and Carcinogenesis ,3. Good health - Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
25. Identification of a new gene regulatory circuit involving B cell receptor activated signaling using a combined analysis of experimental, clinical and global gene expression data
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Schrader, A., Meyer, Katharina, Walther, N., Stolz, A., Feist, M., Hand, E., Bonin, F. von, Evers, Maurits, Kohler, Christian, Shirneshan, K., Vockerodt, M., Klapper, W., Szczepanowski, M., Murray, P. G., Bastians, H., Trümper, Lorenz, Spang, Rainer, and Kube, Dieter
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hemic and lymphatic diseases ,610 Medizin ,500 Naturwissenschaften ,NF-KAPPA-B ,BURKITTS-LYMPHOMA ,INDUCED APOPTOSIS ,DIFFERENTIAL EXPRESSION ,PATHWAY ACTIVATION ,MEDIATED APOPTOSIS ,CYCLE REGULATION ,IN-VITRO ,MITOSIS ,TARGET ,lymphoma ,B cell receptor signaling ,guided clustering ,cell cycle delay ,chromosomal aberrations ,3. Good health - Abstract
To discover new regulatory pathways in B lymphoma cells, we performed a combined analysis of experimental, clinical and global gene expression data. We identified a specific cluster of genes that was coherently expressed in primary lymphoma samples and suppressed by activation of the B cell receptor (BCR) through aIgM treatment of lymphoma cells in vitro. This gene cluster, which we called BCR. 1, includes numerous cell cycle regulators. A reduced expression of BCR. 1 genes after BCR activation was observed in different cell lines and also in CD10(+) germinal center B cells. We found that BCR activation led to a delayed entry to and progression of mitosis and defects in metaphase. Cytogenetic changes were detected upon long-term aIgM treatment. Furthermore, an inverse correlation of BCR. 1 genes with c-Myc co-regulated genes in distinct groups of lymphoma patients was observed. Finally, we showed that the BCR. 1 index discriminates activated B cell-like and germinal centre B cell-like diffuse large B cell lymphoma supporting the functional relevance of this new regulatory circuit and the power of guided clustering for biomarker discovery.
26. Jairus begehrt, Jesus gewährt
- Author
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Ahle, Johann Rudolf, 1625-1673, composer. and Vockerodt, M. Johann, author.
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- 1961
27. Mein bester freund, mein Jesus weint
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Ahle, Johann Rudolf, 1625-1673, composer. and Vockerodt, M. Johann, author.
- Published
- 1961
28. Splitter-Richter-Bösewichter
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Ahle, Johann Rudolf, 1625-1673, composer. and Vockerodt, M. Johann, author.
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- 1961
29. Dual Inhibition of PI3 Kinase and MAP Kinase Signaling Pathways in Intrahepatic Cholangiocellular Carcinoma Cell Lines Leads to Proliferation Arrest but Not Apoptosis.
- Author
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Schüler J, Vockerodt M, Salehzadeh N, Becker J, and Wilting J
- Abstract
Cholangiocellular carcinoma (CCA) is the second most common primary liver cancer, with increasing incidence worldwide and inadequate therapeutic options. Intra- and extrahepatic bile ducts have distinctly different embryonic origins and developmental behavior, and accordingly, intra- and extrahepatic CCAs (ICC vs. ECC) are molecularly different. A promising strategy in oncotherapy is targeted therapy, targeting proteins that regulate cell survival and proliferation, such as the MAPK/ERK and PI3K/AKT/mTOR signaling pathways. Inhibitors of these pathways have been tested previously in CCA cell lines. However, these cell lines could not be clearly assigned to ICC or ECC, and the results indicated apoptosis induction by targeted therapeutics. We tested targeted therapeutics (selumetinib, MK2206) in three defined ICC cell lines (HuH28, RBE, SSP25). We observed additive effects of the dual inhibition of the two pathways, in accordance with the inhibition of phospho-AKT and phospho-ERK1/2 expression. Proliferation was blocked more effectively with dual inhibition than with each single inhibition, but cell numbers did not drop below baseline. Accordingly, we observed G1 phase arrest but not apoptosis or cell death (measured by cleaved caspase-3, AIFM1 regulation, sub-G0/G1 phase). We conclude that the dual inhibition of the MAPK/ERK and PI3K/AKT/mTOR pathways is highly effective to block the proliferation of ICC cell lines in vitro; however, potential clinical applications must be critically examined, as a proliferation block could also induce resistance to standard therapies.
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- 2024
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30. High CD206 levels in Hodgkin lymphoma-educated macrophages are linked to matrix-remodeling and lymphoma dissemination.
- Author
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Arlt A, von Bonin F, Rehberg T, Perez-Rubio P, Engelmann JC, Limm K, Reinke S, Dullin C, Sun X, Specht R, Maulhardt M, Linke F, Bunt G, Klapper W, Vockerodt M, Wilting J, Pukrop T, Dettmer K, Gronwald W, Oefner PJ, Spang R, and Kube D
- Subjects
- Animals, Antigens, CD metabolism, Antigens, Differentiation, Myelomonocytic metabolism, B7-H1 Antigen metabolism, CD40 Antigens metabolism, Cell Differentiation drug effects, Cell Line, Tumor, Chick Embryo, Chorioallantoic Membrane metabolism, Chorioallantoic Membrane pathology, Collagen Type I metabolism, Culture Media, Conditioned metabolism, Fluorescent Antibody Technique, Hodgkin Disease immunology, Hodgkin Disease pathology, Humans, Interleukin-13 metabolism, Lymphoma, B-Cell immunology, Lymphoma, B-Cell pathology, Macrophages drug effects, Membrane Glycoproteins immunology, Monocytes metabolism, Neoplasm Metastasis immunology, Proteome genetics, Proteome metabolism, RNA-Seq, Receptors, Cell Surface metabolism, Receptors, Immunologic immunology, Up-Regulation, Xenograft Model Antitumor Assays, Culture Media, Conditioned pharmacology, Hodgkin Disease metabolism, Lymphoma, B-Cell metabolism, Macrophages metabolism, Membrane Glycoproteins metabolism, Receptors, Immunologic metabolism, Tumor Microenvironment
- Abstract
Macrophages (Mφ) are abundantly present in the tumor microenvironment and may predict outcome in solid tumors and defined lymphoma subtypes. Mφ heterogeneity, the mechanisms of their recruitment, and their differentiation into lymphoma-promoting, alternatively activated M2-like phenotypes are still not fully understood. Therefore, further functional studies are required to understand biological mechanisms associated with human tumor-associated Mφ (TAM). Here, we show that the global mRNA expression and protein abundance of human Mφ differentiated in Hodgkin lymphoma (HL)-conditioned medium (CM) differ from those of Mφ educated by conditioned media from diffuse large B-cell lymphoma (DLBCL) cells or, classically, by macrophage colony-stimulating factor (M-CSF). Conditioned media from HL cells support TAM differentiation through upregulation of surface antigens such as CD40, CD163, CD206, and PD-L1. In particular, RNA and cell surface protein expression of mannose receptor 1 (MRC1)/CD206 significantly exceed the levels induced by classical M-CSF stimulation in M2-like Mφ; this is regulated by interleukin 13 to a large extent. Functionally, high CD206 enhances mannose-dependent endocytosis and uptake of type I collagen. Together with high matrix metalloprotease9 secretion, HL-TAMs appear to be active modulators of the tumor matrix. Preclinical in ovo models show that co-cultures of HL cells with monocytes or Mφ support dissemination of lymphoma cells via lymphatic vessels, while tumor size and vessel destruction are decreased in comparison with lymphoma-only tumors. Immunohistology of human HL tissues reveals a fraction of cases feature large numbers of CD206-positive cells, with high MRC1 expression being characteristic of HL-stage IV. In summary, the lymphoma-TAM interaction contributes to matrix-remodeling and lymphoma cell dissemination., (© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)
- Published
- 2020
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31. Regulation of S1PR2 by the EBV oncogene LMP1 in aggressive ABC-subtype diffuse large B-cell lymphoma.
- Author
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Vockerodt M, Vrzalikova K, Ibrahim M, Nagy E, Margielewska S, Hollows R, Lupino L, Tooze R, Care M, Simmons W, Schrader A, Perry T, Abdullah M, Foster S, Reynolds G, Dowell A, Rudzki Z, Krappmann D, Kube D, Woodman C, Wei W, Taylor G, and Murray PG
- Subjects
- CD40 Antigens genetics, CD40 Antigens metabolism, Cell Line, Tumor, Cell Transformation, Viral, Databases, Genetic, Epstein-Barr Virus Infections mortality, Gene Expression Regulation, Neoplastic, Herpesvirus 4, Human genetics, Host-Pathogen Interactions, Humans, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse mortality, Lymphoma, Large B-Cell, Diffuse virology, Phosphatidylinositol 3-Kinase metabolism, Prognosis, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction, Sphingosine-1-Phosphate Receptors genetics, Viral Matrix Proteins genetics, Epstein-Barr Virus Infections virology, Herpesvirus 4, Human metabolism, Lymphoma, Large B-Cell, Diffuse metabolism, Sphingosine-1-Phosphate Receptors metabolism, Viral Matrix Proteins metabolism
- Abstract
The Epstein-Barr virus (EBV) is found almost exclusively in the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), yet its contribution to this tumour remains poorly understood. We have focused on the EBV-encoded latent membrane protein-1 (LMP1), a constitutively activated CD40 homologue expressed in almost all EBV-positive DLBCLs and which can disrupt germinal centre (GC) formation and drive lymphomagenesis in mice. Comparison of the transcriptional changes that follow LMP1 expression with those that follow transient CD40 signalling in human GC B cells enabled us to define pathogenic targets of LMP1 aberrantly expressed in ABC-DLBCL. These included the down-regulation of S1PR2, a sphingosine-1-phosphate (S1P) receptor that is transcriptionally down-regulated in ABC-DLBCL, and when genetically ablated leads to DLBCL in mice. Consistent with this, we found that LMP1-expressing primary ABC-DLBCLs were significantly more likely to lack S1PR2 expression than were LMP1-negative tumours. Furthermore, we showed that the down-regulation of S1PR2 by LMP1 drives a signalling loop leading to constitutive activation of the phosphatidylinositol-3-kinase (PI3-K) pathway. Finally, core LMP1-PI3-K targets were enriched for lymphoma-related transcription factors and genes associated with shorter overall survival in patients with ABC-DLBCL. Our data identify a novel function for LMP1 in aggressive DLBCL. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
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- 2019
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32. Co-Expression of the Epstein-Barr Virus-Encoded Latent Membrane Proteins and the Pathogenesis of Classic Hodgkin Lymphoma.
- Author
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Vrzalikova K, Ibrahim M, Nagy E, Vockerodt M, Perry T, Wei W, Woodman C, and Murray P
- Abstract
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.
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- 2018
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33. Identification of a new gene regulatory circuit involving B cell receptor activated signaling using a combined analysis of experimental, clinical and global gene expression data.
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Schrader A, Meyer K, Walther N, Stolz A, Feist M, Hand E, von Bonin F, Evers M, Kohler C, Shirneshan K, Vockerodt M, Klapper W, Szczepanowski M, Murray PG, Bastians H, Trümper L, Spang R, and Kube D
- Subjects
- Cell Cycle genetics, Cell Line, Tumor, Cohort Studies, Gene Expression Profiling, Germinal Center metabolism, Germinal Center pathology, Humans, Lymphocyte Activation, Lymphoma, Large B-Cell, Diffuse pathology, Proto-Oncogene Proteins c-bcl-6, Proto-Oncogene Proteins c-myc, Receptors, Antigen, B-Cell metabolism, Signal Transduction genetics, Tumor Microenvironment, B-Lymphocytes metabolism, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Lymphoma, Large B-Cell, Diffuse genetics, Receptors, Antigen, B-Cell genetics
- Abstract
To discover new regulatory pathways in B lymphoma cells, we performed a combined analysis of experimental, clinical and global gene expression data. We identified a specific cluster of genes that was coherently expressed in primary lymphoma samples and suppressed by activation of the B cell receptor (BCR) through αIgM treatment of lymphoma cells in vitro. This gene cluster, which we called BCR.1, includes numerous cell cycle regulators. A reduced expression of BCR.1 genes after BCR activation was observed in different cell lines and also in CD10+ germinal center B cells. We found that BCR activation led to a delayed entry to and progression of mitosis and defects in metaphase. Cytogenetic changes were detected upon long-term αIgM treatment. Furthermore, an inverse correlation of BCR.1 genes with c-Myc co-regulated genes in distinct groups of lymphoma patients was observed. Finally, we showed that the BCR.1 index discriminates activated B cell-like and germinal centre B cell-like diffuse large B cell lymphoma supporting the functional relevance of this new regulatory circuit and the power of guided clustering for biomarker discovery., Competing Interests: The authors declare no competing financial interests.
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- 2016
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34. The Epstein-Barr virus and the pathogenesis of lymphoma.
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Vockerodt M, Yap LF, Shannon-Lowe C, Curley H, Wei W, Vrzalikova K, and Murray PG
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- Animals, Biopsy, Epstein-Barr Virus Infections complications, Epstein-Barr Virus Infections immunology, Epstein-Barr Virus Infections pathology, Herpesvirus 4, Human immunology, Host-Pathogen Interactions, Humans, Lymphoma immunology, Lymphoma pathology, Pathology, Molecular methods, Predictive Value of Tests, Prognosis, Risk Factors, Virology methods, Virulence, Epstein-Barr Virus Infections virology, Herpesvirus 4, Human pathogenicity, Lymphoma virology
- Abstract
Since the discovery in 1964 of the Epstein-Barr virus (EBV) in African Burkitt lymphoma, this virus has been associated with a remarkably diverse range of cancer types. Because EBV persists in the B cells of the asymptomatic host, it can easily be envisaged how it contributes to the development of B-cell lymphomas. However, EBV is also found in other cancers, including T-cell/natural killer cell lymphomas and several epithelial malignancies. Explaining the aetiological role of EBV is challenging, partly because the virus probably contributes differently to each tumour and partly because the available disease models cannot adequately recapitulate the subtle variations in the virus-host balance that exist between the different EBV-associated cancers. A further challenge is to identify the co-factors involved; because most persistently infected individuals will never develop an EBV-associated cancer, the virus cannot be working alone. This article will review what is known about the contribution of EBV to lymphoma development., (Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
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- 2015
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35. Epstein-Barr virus and the origin of Hodgkin lymphoma.
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Vockerodt M, Cader FZ, Shannon-Lowe C, and Murray P
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- Epstein-Barr Virus Infections, Humans, Reed-Sternberg Cells, Herpesvirus 4, Human, Hodgkin Disease virology
- Abstract
Although Epstein-Barr virus (EBV) is present in the malignant Hodgkin/Reed-Sternberg (HRS) cells of a proportion of cases of classical Hodgkin lymphoma (cHL), how the virus contributes to the pathogenesis of this disease remains poorly defined. It is clear from the studies of other EBV-associated cancers that the virus is usually not sufficient for tumor development and that other oncogenic co-factors are required. This article reviews what is known about the contribution of EBV to the pathogenesis of cHL and focuses on emerging evidence implicating chronic inflammation as a potential oncogenic co-factor in this malignancy.
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- 2014
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36. Epstein-Barr virus, the germinal centre and the development of Hodgkin's lymphoma.
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Mohamed G, Vrzalikova K, Cader FZ, Vockerodt M, Nagy E, Flodr P, Yap LF, Diepstra A, Kluin PM, Rosati S, and Murray P
- Subjects
- Adult, B-Lymphocytes immunology, Cell Differentiation immunology, Epstein-Barr Virus Infections virology, Female, Hodgkin Disease immunology, Humans, Male, Middle Aged, Pseudolymphoma virology, Receptors, Antigen, B-Cell immunology, Viral Matrix Proteins, Virus Replication immunology, Young Adult, B-Lymphocytes virology, Germinal Center immunology, Germinal Center virology, Herpesvirus 4, Human immunology, Hodgkin Disease virology
- Abstract
The relationship between Epstein-Barr virus (EBV) and the germinal centre (GC) of the asymptomatic host remains an enigma. The occasional appearance of EBV-positive germinal centres in some patients, particularly those with a history of immunosuppression, suggests that EBV numbers in the GC are subject to immune control. The relationship, if any, between lymphoid hyperplasia with EBV-positive germinal centres and subsequent or concurrent lymphomagenesis remains to be clarified. As far as the development of EBV-associated Hodgkin's lymphoma is concerned, the suppression of virus replication, mediated by LMP1 on the one hand, and the loss of B-cell receptor signalling on the other, appears to be an important pathogenic mechanism. A further important emerging concept is that alterations in the microenvironment of the EBV-infected B-cell may be important for lymphomagenesis., (© 2014 The Authors.)
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- 2014
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37. The EBV oncogene LMP1 protects lymphoma cells from cell death through the collagen-mediated activation of DDR1.
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Cader FZ, Vockerodt M, Bose S, Nagy E, Brundler MA, Kearns P, and Murray PG
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- B-Lymphocytes physiology, Burkitt Lymphoma genetics, Burkitt Lymphoma pathology, Cell Death physiology, Cells, Cultured, Collagen metabolism, Discoidin Domain Receptor 1, Epstein-Barr Virus Infections pathology, Gene Expression Regulation, Viral, Gene Knockdown Techniques, Germinal Center cytology, Hodgkin Disease pathology, Humans, Phosphorylation physiology, Receptor Protein-Tyrosine Kinases genetics, Reed-Sternberg Cells cytology, Reed-Sternberg Cells physiology, Tumor Microenvironment physiology, B-Lymphocytes cytology, Epstein-Barr Virus Infections genetics, Herpesvirus 4, Human genetics, Hodgkin Disease genetics, Receptor Protein-Tyrosine Kinases metabolism, Viral Matrix Proteins genetics
- Abstract
The malignant Hodgkin and Reed-Sternberg (HRS) cells of Hodgkin lymphoma are surrounded by a tumor microenvironment that is composed of a variety of cell types, as well as noncellular components such as collagen. Although HRS cells harbor oncogenic Epstein-Barr virus (EBV) in approximately 50% of cases, it is not known if the tumor microenvironment contributes to EBV-driven lymphomagenesis. We show that expression of the EBV-encoded latent membrane protein-1 (LMP1) in primary human germinal center B cells, the presumed progenitors of HRS cells, upregulates discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase activated by collagen. We also show that HRS cells intimately associated with collagen frequently overexpress DDR1 and that short-term exposure to collagen is sufficient to activate DDR1 in Hodgkin lymphoma-derived cell lines. The ectopic expression of DDR1 significantly increased the survival of collagen-treated DG75 Burkitt lymphoma cells, following etoposide treatment. Conversely, knockdown of DDR1 significantly decreased the survival of collagen-treated L428 Hodgkin lymphoma cells in the absence of specific apoptotic stimulus, suggesting that DDR1 also influences baseline survival. Our results identify a hitherto unknown function for collagen in protecting Hodgkin lymphoma cells from apoptosis and suggest an important contribution of the tumor microenvironment in promoting the oncogenic effects of EBV.
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- 2013
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38. Suppression of the LMP2A target gene, EGR-1, protects Hodgkin's lymphoma cells from entry to the EBV lytic cycle.
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Vockerodt M, Wei W, Nagy E, Prouzova Z, Schrader A, Kube D, Rowe M, Woodman CB, and Murray PG
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- B-Lymphocytes metabolism, Burkitt Lymphoma metabolism, Burkitt Lymphoma pathology, Burkitt Lymphoma virology, Cell Line, Tumor, Cytopathogenic Effect, Viral, Early Growth Response Protein 1 genetics, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases metabolism, Gene Expression Profiling methods, Gene Expression Regulation, Neoplastic, Herpesvirus 4, Human genetics, Herpesvirus 4, Human pathogenicity, Hodgkin Disease genetics, Hodgkin Disease pathology, Hodgkin Disease virology, Humans, Oligonucleotide Array Sequence Analysis, Receptors, Antigen, B-Cell metabolism, Reed-Sternberg Cells pathology, Reed-Sternberg Cells virology, Trans-Activators metabolism, Transfection, Up-Regulation, Viral Matrix Proteins genetics, Early Growth Response Protein 1 metabolism, Herpesvirus 4, Human metabolism, Hodgkin Disease metabolism, Reed-Sternberg Cells metabolism, Viral Matrix Proteins metabolism
- Abstract
Hodgkin's lymphoma is unusual among B cell lymphomas, in so far as the malignant Hodgkin/Reed-Sternberg (HRS) cells lack a functional B cell receptor (BCR), as well as many of the required downstream signalling components. In Epstein-Barr virus (EBV)-positive cases of Hodgkin's lymphoma, HRS cells express the viral latent membrane proteins (LMP)-1 and -2A. LMP2A is thought to contribute to the pathogenesis of Hodgkin's lymphoma by providing a surrogate BCR-like survival signal. However, LMP2A has also been shown to induce the virus-replicative cycle in B cells, an event presumably incompatible with lymphomagenesis. In an attempt to resolve this apparent paradox, we compared the transcriptional changes observed in primary HRS cells with those induced by LMP2A and by BCR activation in primary human germinal centre (GC) B cells, the presumed progenitors of HRS cells. We found a subset of genes that were up-regulated by both LMP2A expression and BCR activation but which were down-regulated in primary HRS cells. These genes included EGR1, an immediate-early gene that is required for BCR-induced entry to the virus-replicative cycle. We present data supporting a model for the pathogenesis of EBV-positive Hodgkin's lymphoma in which LMP2A-expressing HRS cells lacking BCR signalling functions cannot induce EGR1 and are consequently protected from entry to the virus lytic cycle. The primary microarray data are available from GEO (http://www.ncbi.nlm.nih.gov/geo/) under series Accession No 46143., (Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
- Published
- 2013
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39. Induction of interferon-stimulated genes on the IL-4 response axis by Epstein-Barr virus infected human b cells; relevance to cellular transformation.
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Smith N, Tierney R, Wei W, Vockerodt M, Murray PG, Woodman CB, and Rowe M
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- B-Lymphocytes pathology, CD40 Ligand immunology, CD40 Ligand pharmacology, Cell Line, Tumor, Cell Transformation, Viral drug effects, Gene Expression Profiling, Hodgkin Disease genetics, Hodgkin Disease metabolism, Humans, Interferons metabolism, Interleukin-4 pharmacology, Lymphocyte Activation drug effects, Lymphocyte Activation genetics, Lymphocyte Activation immunology, Signal Transduction, Transcriptome, Viral Matrix Proteins metabolism, B-Lymphocytes metabolism, B-Lymphocytes virology, Cell Transformation, Viral genetics, Gene Expression Regulation drug effects, Herpesvirus 4, Human physiology, Interferon Regulatory Factors genetics, Interleukin-4 metabolism
- Abstract
Epstein-Barr virus (EBV) is an oncogenic virus that is associated with the pathogenesis of several human lymphoid malignancies, including Hodgkin's lymphoma. Infection of normal resting B cells with EBV results in activation to lymphoblasts that are phenotypically similar to those generated by physiological stimulation with CD40L plus IL-4. One important difference is that infection leads to the establishment of permanently growing lymphoblastoid cell lines, whereas CD40L/IL-4 blasts have finite proliferation lifespans. To identify early events which might later determine why EBV infected blasts go on to establish transformed cell lines, we performed global transcriptome analyses on resting B cells and on EBV and CD40L/IL-4 blasts after 7 days culture. As anticipated there was considerable overlap in the transcriptomes of the two types of lymphoblasts when compared to the original resting B cells, reflecting common changes associated with lymphocyte activation and proliferation. Of interest to us was a subset of 255 genes that were differentially expressed between EBV and CD40L/IL-4 blasts. Genes which were more highly expressed in EBV blasts were substantially and significantly enriched for a set of interferon-stimulated genes which on further in silico analyses were found to be repressed by IL-4 in other cell contexts and to be up-regulated in micro-dissected malignant cells from Hodgkin's lymphoma biopsies when compared to their normal germinal center cell counterparts. We hypothesized that EBV and IL-4 were targeting and discordantly regulating a common set of genes. This was supported experimentally in our B cell model where IL-4 stimulation partially reversed transcriptional changes which follow EBV infection and it impaired the efficiency of EBV-induced B cell transformation. Taken together, these data suggest that the discordant regulation of interferon and IL-4 pathway genes by EBV that occurs early following infection of B cells has relevance to the development or maintenance of an EBV-associated malignancy.
- Published
- 2013
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40. Aberrant lymphocyte enhancer-binding factor 1 expression is characteristic for sporadic Burkitt's lymphoma.
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Walther N, Ulrich A, Vockerodt M, von Bonin F, Klapper W, Meyer K, Eberth S, Pukrop T, Spang R, Trümper L, and Kube D
- Subjects
- Burkitt Lymphoma genetics, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Genes, Neoplasm genetics, Humans, Lymphoid Enhancer-Binding Factor 1 genetics, Oligonucleotide Array Sequence Analysis, Palatine Tonsil metabolism, Palatine Tonsil pathology, Burkitt Lymphoma metabolism, Burkitt Lymphoma pathology, Lymphoid Enhancer-Binding Factor 1 metabolism
- Abstract
Burkitt's lymphoma (BL) is a highly malignant, aggressive non-Hodgkin's lymphoma derived from germinal center B cells. Recently, global gene expression profiling of patient samples led to a molecular definition of BL with lymphocyte enhancer-binding factor 1 (LEF1) as a signature gene. Herein, we report the expression of nucleic LEF1 in 15 of 18 patients with BL and the identification of LEF1 target genes. Germinal center B cells were devoid of detectable nuclear LEF1 expression, as were mantle cell lymphoma (0 of 5), marginal zone lymphoma (0 of 6), follicular lymphoma (0 of 12), and diffuse large B-cell lymphoma (1 of 31). Whole-genome gene expression profiling after transient knockdown of LEF1 in BL cell lines identified new LEF1 target genes; these LEF1 targets are enriched with genes associated with cancers. The expression of LEF1 and LEF1-regulated genes in primary BL suggests that LEF1 is not only aberrantly expressed but also transcriptionally active. This study supports a functionally important role for LEF1 and its target genes in BLs., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
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41. Global gene expression changes of in vitro stimulated human transformed germinal centre B cells as surrogate for oncogenic pathway activation in individual aggressive B cell lymphomas.
- Author
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Schrader A, Meyer K, von Bonin F, Vockerodt M, Walther N, Hand E, Ulrich A, Matulewicz K, Lenze D, Hummel M, Kieser A, Engelke M, Trümper L, and Kube D
- Abstract
Background: Aggressive Non-Hodgkin lymphomas (NHL) are a group of lymphomas derived from germinal centre B cells which display a heterogeneous pattern of oncogenic pathway activation. We postulate that specific immune response associated signalling, affecting gene transcription networks, may be associated with the activation of different oncogenic pathways in aggressive Non-Hodgkin lymphomas (NHL)., Methodology: The B cell receptor (BCR), CD40, B-cell activating factor (BAFF)-receptors and Interleukin (IL) 21 receptor and Toll like receptor 4 (TLR4) were stimulated in human transformed germinal centre B cells by treatment with anti IgM F(ab)2-fragments, CD40L, BAFF, IL21 and LPS respectively. The changes in gene expression following the activation of Jak/STAT, NF-кB, MAPK, Ca2+ and PI3K signalling triggered by these stimuli was assessed using microarray analysis. The expression of top 100 genes which had a change in gene expression following stimulation was investigated in gene expression profiles of patients with Aggressive non-Hodgkin Lymphoma (NHL)., Results: αIgM stimulation led to the largest number of changes in gene expression, affecting overall 6596 genes. While CD40L stimulation changed the expression of 1194 genes and IL21 stimulation affected 902 genes, only 283 and 129 genes were modulated by lipopolysaccharide or BAFF receptor stimulation, respectively. Interestingly, genes associated with a Burkitt-like phenotype, such as MYC, BCL6 or LEF1, were affected by αIgM. Unique and shared gene expression was delineated. NHL-patients were sorted according to their similarity in the expression of TOP100 affected genes to stimulated transformed germinal centre B cells The αIgM gene module discriminated individual DLBCL in a similar manner to CD40L or IL21 gene modules. DLBCLs with low module activation often carry chromosomal MYC aberrations. DLBCLs with high module activation show strong expression of genes involved in cell-cell communication, immune responses or negative feedback loops. Using chemical inhibitors for selected kinases we show that mitogen activated protein kinase- and phosphoinositide 3 kinase-signalling are dominantly involved in regulating genes included in the αIgM gene module., Conclusion: We provide an in vitro model system to investigate pathway activation in lymphomas. We defined the extent to which different immune response associated pathways are responsible for differences in gene expression which distinguish individual DLBCL cases. Our results support the view that tonic or constitutively active MAPK/ERK pathways are an important part of oncogenic signalling in NHL. The experimental model can now be applied to study the therapeutic potential of deregulated oncogenic pathways and to develop individual treatment strategies for lymphoma patients.
- Published
- 2012
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42. Hypomethylation and Over-Expression of the Beta Isoform of BLIMP1 is Induced by Epstein-Barr Virus Infection of B Cells; Potential Implications for the Pathogenesis of EBV-Associated Lymphomas.
- Author
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Vrzalikova K, Leonard S, Fan Y, Bell A, Vockerodt M, Flodr P, Wright KL, Rowe M, Tao Q, and Murray PG
- Abstract
B-lymphocyte-induced maturation protein 1 (BLIMP1) exists as two major isoforms, α and β, which arise from alternate promoters. Inactivation of the full length BLIMP1α isoform is thought to contribute to B cell lymphomagenesis by blocking post-germinal centre (GC) B cell differentiation. In contrast, the shorter β isoform is functionally impaired and over-expressed in several haematological malignancies, including diffuse large B cell lymphomas (DLBCL). We have studied the influence on BLIMP1β expression of the Epstein-Barr virus (EBV), a human herpesvirus that is implicated in the pathogenesis of several GC-derived lymphomas, including a subset of DLBCL and Hodgkin's lymphoma (HL). We show that BLIMP1β expression is increased following the EBV infection of normal human tonsillar GC B cells. We also show that this change in expression is accompanied by hypomethylation of the BLIMP1β-specific promoter. Furthermore, we confirmed previous reports that the BLIMP1β promoter is hypomethylated in DLBCL cell lines and show for the first time that BLIMP1β is hypomethylated in the Hodgkin/Reed-Sternberg (HRS) cells of HL. Our results provide evidence in support of a role for BLIMP1β in the pathogenesis of EBV-associated B cell lymphomas.
- Published
- 2012
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43. High Myc activity is an independent negative prognostic factor for diffuse large B cell lymphomas.
- Author
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Schrader A, Bentink S, Spang R, Lenze D, Hummel M, Kuo M, Arrand JR, Murray PG, Trümper L, Kube D, and Vockerodt M
- Subjects
- Base Sequence, Blotting, Western, Cell Line, Tumor, DNA Primers, Fluorescent Antibody Technique, Humans, Lymphoma, Large B-Cell, Diffuse pathology, Prognosis, Proto-Oncogene Proteins c-myc genetics, Real-Time Polymerase Chain Reaction, Lymphoma, Large B-Cell, Diffuse metabolism, Proto-Oncogene Proteins c-myc metabolism
- Abstract
Gene expression profiling has recently enabled the reclassification of aggressive non-Hodgkin lymphomas (aNHL) into distinct subgroups. In Burkitt lymphoma (BL) aberrant c-Myc activity results from IG-MYC translocations. However, MYC aberrations are not limited to BLs and then have a negative prognostic impact. In this study, we investigated to which extent aberrant c-Myc activity plays a functional role in other aNHL and whether it is independent from MYC translocations. Based on a combined microarray analysis of human germinal center (GC) B cells transfected with c-Myc and 220 aNHLs cases, we developed a "c-Myc index." This index measures the extent to which lymphomas express c-Myc responsive genes. It comprises genes that are affected in a variety of tumors compared to normal tissue. This supports the view that aberrant c-Myc expression in GC B cells triggers a tumor-like expression pattern. As expected, the "c-Myc index" is very high in molecular Burkitt lymphoma (mBL), but more importantly also high within other aNHL. It constitutes a negative prognostic marker independent of established risk factors and of the presence of a MYC translocation. Our data provide new insights into the role of c-Myc activity in different lymphomas and raises the question of treatment changes for those patients under risk., (Copyright © 2011 UICC.)
- Published
- 2012
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44. Epigenetic and transcriptional changes which follow Epstein-Barr virus infection of germinal center B cells and their relevance to the pathogenesis of Hodgkin's lymphoma.
- Author
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Leonard S, Wei W, Anderton J, Vockerodt M, Rowe M, Murray PG, and Woodman CB
- Subjects
- B-Lymphocytes virology, Cells, Cultured, DNA (Cytosine-5-)-Methyltransferase 1, DNA (Cytosine-5-)-Methyltransferases biosynthesis, DNA Methylation, DNA Methyltransferase 3A, Gene Expression Profiling, Germinal Center virology, Hodgkin Disease immunology, Hodgkin Disease pathology, Humans, Viral Matrix Proteins metabolism, DNA Methyltransferase 3B, B-Lymphocytes immunology, Epigenesis, Genetic, Gene Expression Regulation, Germinal Center immunology, Herpesvirus 4, Human pathogenicity, Hodgkin Disease virology, Transcription, Genetic
- Abstract
Although Epstein-Barr virus (EBV) usually establishes an asymptomatic lifelong infection, it is also implicated in the development of germinal center (GC) B-cell-derived malignancies, including Hodgkin's lymphoma (HL). Following primary infection, EBV remains latent in the memory B-cell population, where host-driven methylation of viral DNA contributes to the repression of viral gene expression. However, it is still unclear how EBV harnesses the cell's methylation machinery in B cells, how this contributes to viral persistence, and what impact this has on the methylation of cellular genes. We show that EBV infection of GC B cells is followed by upregulation of the DNA methyltransferase DNMT3A and downregulation of DNMT3B and DNMT1. We show that the EBV latent membrane protein 1 (LMP1) oncogene downregulates DNMT1 and that DNMT3A binds to the viral promoter Wp. Genome-wide promoter arrays performed with these cells showed that EBV-associated methylation changes in cellular genes were not randomly distributed across the genome but clustered at chromosomal locations, consistent with an instructive pattern of methylation, and were in part determined by promoter CpG content. Both DNMT3B and DNMT1 were downregulated and DNMT3A was upregulated in HL cell lines, recapitulating the pattern of expression observed following EBV infection of GC B cells. We also found, by using gene expression profiling, that genes differentially expressed following EBV infection of GC B cells were significantly enriched for those reported to be differentially expressed in HL. These observations suggest that EBV-infected GC B cells are a useful model for studying virus-associated changes contributing to the pathogenesis of HL.
- Published
- 2011
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45. Down-regulation of BLIMP1α by the EBV oncogene, LMP-1, disrupts the plasma cell differentiation program and prevents viral replication in B cells: implications for the pathogenesis of EBV-associated B-cell lymphomas.
- Author
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Vrzalikova K, Vockerodt M, Leonard S, Bell A, Wei W, Schrader A, Wright KL, Kube D, Rowe M, Woodman CB, and Murray PG
- Subjects
- B-Lymphocytes metabolism, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Blotting, Western, Cell Transformation, Viral, Cells, Cultured, Child, Epstein-Barr Virus Infections complications, Epstein-Barr Virus Infections genetics, Epstein-Barr Virus Infections virology, Gene Expression Profiling, Germinal Center, Humans, Immunoenzyme Techniques, Lymphoma, B-Cell pathology, Oligonucleotide Array Sequence Analysis, Palatine Tonsil cytology, Palatine Tonsil metabolism, Plasma Cells metabolism, Positive Regulatory Domain I-Binding Factor 1, RNA, Messenger genetics, Repressor Proteins genetics, Reverse Transcriptase Polymerase Chain Reaction, Viral Matrix Proteins genetics, Virus Latency, Virus Replication, B-Lymphocytes virology, Cell Differentiation, Herpesvirus 4, Human physiology, Lymphoma, B-Cell etiology, Plasma Cells pathology, Repressor Proteins metabolism, Viral Matrix Proteins metabolism
- Abstract
An important pathogenic event in Epstein-Barr virus (EBV)-associated lymphomas is the suppression of virus replication, which would otherwise lead to cell death. Because virus replication in B cells is intimately linked to their differentiation toward plasma cells, we asked whether the physiologic signals that drive normal B-cell differentiation are absent in EBV-transformed cells. We focused on BLIMP1α, a transcription factor that is required for plasma cell differentiation and that is inactivated in diffuse large B-cell lymphomas. We show that BLIMP1α expression is down-regulated after EBV infection of primary germinal center B cells and that the EBV oncogene, latent membrane protein-1 (LMP-1), is alone capable of inducing this down-regulation in these cells. Furthermore, the down-regulation of BLIMP1α by LMP-1 was accompanied by a partial disruption of the BLIMP1α transcriptional program, including the aberrant induction of MYC, the repression of which is required for terminal differentiation. Finally, we show that the ectopic expression of BLIMP1α in EBV-transformed cells can induce the viral lytic cycle. Our results suggest that LMP-1 expression in progenitor germinal center B cells could contribute to the pathogenesis of EBV-associated lymphomas by down-regulating BLIMP1α, in turn preventing plasma cell differentiation and induction of the viral lytic cycle.
- Published
- 2011
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46. The contribution of the Epstein-Barr virus to the pathogenesis of childhood lymphomas.
- Author
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Cader FZ, Kearns P, Young L, Murray P, and Vockerodt M
- Subjects
- Antiviral Agents therapeutic use, Burkitt Lymphoma etiology, Burkitt Lymphoma virology, Child, Hodgkin Disease etiology, Hodgkin Disease virology, Humans, Immunotherapy, Adoptive, Lymphoma virology, Lymphoma, B-Cell etiology, Lymphoma, B-Cell virology, Lymphoproliferative Disorders etiology, Lymphoproliferative Disorders virology, Herpesvirus 4, Human isolation & purification, Lymphoma etiology
- Abstract
The Epstein-Barr virus (EBV) is a lymphotropic herpes virus with oncogenetic properties which can lead to the development of lymphomas such as Burkitt's lymphoma (BL), Hodgkin's lymphoma (HL), or post-transplant lymphoma. This review discusses our current understanding of lymphomagenesis in relation to EBV and the potential for targeted therapies., (2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
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47. Evidence for a pathophysiological role of cysteinyl leukotrienes in classical Hodgkin lymphoma.
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Schain F, Tryselius Y, Sjöberg J, Porwit A, Backman L, Malec M, Xu D, Vockerodt M, Baumforth KR, Wei W, Murray PG, Björkholm M, and Claesson HE
- Subjects
- Adolescent, Adult, Aged, Calcium Signaling, Cell Line, Tumor, Child, Child, Preschool, Female, Hodgkin Disease metabolism, Humans, Immunohistochemistry, Leukotriene D4 pharmacology, Leukotrienes chemistry, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Polymerase Chain Reaction, Receptors, Leukotriene genetics, Receptors, Leukotriene metabolism, Cysteine chemistry, Hodgkin Disease physiopathology, Leukotrienes physiology
- Abstract
Classical Hodgkin lymphoma (cHL) is characterized histologically by a minority of malignant Hodgkin Reed-Sternberg cells surrounded by abundant inflammatory cells, generally believed to be of major importance in the pathophysiology of the disease. Here, we present data that link inflammatory cell-derived arachidonic acid metabolites, the cysteinyl leukotrienes (CysLT), to the pathogenesis of cHL. Two HL cell lines, L1236 and KMH2, were shown to express functional CysLT(1) receptors, responding with a robust calcium signal upon leukotriene (LT) D(4) challenge. LTD(4) stimulated protein release of tumor necrosis factor-alpha, interleukin-6 and -8 by L1236 cells and interleukin-8 by KMH2 cells. Importantly, all these LTD(4)-induced effects were blocked by the CysLT(1) receptor-specific antagonist zafirlukast. Immunohistochemical studies of cHL biopsies and microarray analysis of microdissected cells revealed that the CysLT(1) receptor is expressed also by primary Hodgkin Reed-Sternberg cells. As these cells are surrounded by CysLT-producing eosinophils, macrophages and mast cells, our results suggest the CysLTs as mediators in the pathogenesis of cHL, contributing to the aberrant cytokine network of this lymphoma., ((c) 2008 Wiley-Liss, Inc.)
- Published
- 2008
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48. Bmi-1 is induced by the Epstein-Barr virus oncogene LMP1 and regulates the expression of viral target genes in Hodgkin lymphoma cells.
- Author
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Dutton A, Woodman CB, Chukwuma MB, Last JI, Wei W, Vockerodt M, Baumforth KR, Flavell JR, Rowe M, Taylor AM, Young LS, and Murray PG
- Subjects
- Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Cell Line, Cell Survival, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Down-Regulation, Gene Expression Profiling, Hodgkin Disease genetics, Hodgkin Disease pathology, Humans, NF-kappa B metabolism, Nuclear Proteins genetics, Polycomb Repressive Complex 1, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins genetics, Repressor Proteins genetics, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism, Up-Regulation, Viral Matrix Proteins genetics, Gene Expression Regulation, Neoplastic, Herpesvirus 4, Human metabolism, Hodgkin Disease metabolism, Nuclear Proteins metabolism, Proto-Oncogene Proteins metabolism, Repressor Proteins metabolism, Viral Matrix Proteins metabolism
- Abstract
Polycomb group (PcG) proteins are chromatin modifiers that are necessary for the maintenance and renewal of embryonic and adult stem cells. However, overexpression of the PcG protein, Bmi-1, causes lymphoma in transgenic mice. We show that Bmi-1 is up-regulated in Hodgkin lymphoma (HL) cells by the Epstein-Barr virus (EBV) oncogene latent membrane protein-1 (LMP1) and that this up-regulation is mediated by NF-kappaB signaling. We also show that Bmi-1 is up-regulated by NF-kappaB in EBV-negative HL cells. Down-regulation of LMP1 and Bmi-1 decreased the survival of HL cells, suggesting that Bmi-1 may mediate the prosurvival effects of LMP1-induced NF-kappaB signaling in HL cells. Transcriptional targets of Bmi-1 were identified after its knockdown in an HL cell line. We show here that Bmi-1 and LMP1 down-regulate the ataxia telangiectasia-mutated (ATM) tumor suppressor and conclude that Bmi-1 contributes to LMP1-induced oncogenesis in HL.
- Published
- 2007
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49. The Epstein-Barr virus oncoprotein latent membrane protein 1 induces expression of the chemokine IP-10: importance of mRNA half-life regulation.
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Vockerodt M, Pinkert D, Smola-Hess S, Michels A, Ransohoff RM, Tesch H, and Kube D
- Subjects
- Amino Acid Motifs, Blotting, Western, CD40 Antigens biosynthesis, Cell Line, Tumor, Dactinomycin pharmacology, Enzyme Activation, Enzyme Inhibitors pharmacology, Humans, Imidazoles pharmacology, Interferon-gamma metabolism, Interleukin-18 metabolism, Lymphoma metabolism, Lymphoma virology, Microscopy, Fluorescence, NF-kappa B metabolism, Plasmids metabolism, Promoter Regions, Genetic, Protein Structure, Tertiary, Pyridines pharmacology, RNA, Messenger metabolism, Signal Transduction, Time Factors, Transcription, Genetic, Transcriptional Activation, Transfection, Viral Matrix Proteins metabolism, p38 Mitogen-Activated Protein Kinases metabolism, Gene Expression Regulation, Neoplastic, Receptors, Chemokine biosynthesis, Receptors, Chemokine physiology, Viral Matrix Proteins physiology
- Abstract
The latent membrane protein 1 (LMP1) of Epstein-Barr Virus (EBV) is the main inducer of immuno-modulatory molecules affecting growth and survival of EBV-infected cells. However, the network of signalling pathways involved remains to be elucidated. Here we show that LMP1 may regulate cellular genes like IFN-gamma-inducible protein-10 kDa (IP-10) not only through transcriptional but also post-transcriptional mechanisms. LMP1-mediated IP-10 expression is independent from IFN-gamma, TNF-alpha or IL-18. Transcriptional activation of IP-10 by LMP1 or CD40 stimulation depends on an NF-kappaB motif within the proximal 435 bp fragment. Carboxy-terminal activating regions 1 or 2 of LMP1 are sufficient to direct IP-10 promoter activation. IP-10 induction is inhibited by blockade of p38/SAPK2 with SB 202190, which results in decreased IP-10 mRNA half-life without affecting IP-10 promoter activity. Thus, LMP1-mediated p38/SAPK2 activation regulates transcript stability. This new mechanism of gene regulation demonstrates the potential of the oncoprotein LMP1 to orchestrate a network of signalling pathways at different regulatory levels including mRNA stability.
- Published
- 2005
- Full Text
- View/download PDF
50. Endogenous MHC class II processing of a viral nuclear antigen after autophagy.
- Author
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Paludan C, Schmid D, Landthaler M, Vockerodt M, Kube D, Tuschl T, and Münz C
- Subjects
- Animals, B-Lymphocytes immunology, CD4-Positive T-Lymphocytes immunology, Cell Line, Cell Line, Transformed, Cell Line, Tumor, Chloroquine pharmacology, Epstein-Barr Virus Nuclear Antigens immunology, Humans, Hydrogen-Ion Concentration, Lysosomes immunology, Lysosomes metabolism, Microsomes metabolism, Phagosomes immunology, Phagosomes ultrastructure, Proteasome Endopeptidase Complex metabolism, Transfection, Antigen Presentation, Autophagy, Epstein-Barr Virus Nuclear Antigens metabolism, Histocompatibility Antigens Class II metabolism, Phagosomes metabolism
- Abstract
CD4+ T cells classically recognize antigens that are endocytosed and processed in lysosomes for presentation on major histocompatibility complex (MHC) class II molecules. Here, endogenous Epstein-Barr virus nuclear antigen 1 (EBNA1) was found to gain access to this pathway by autophagy. On inhibition of lysosomal acidification, EBNA1, the dominant CD4+ T cell antigen of latent Epstein-Barr virus infection, slowly accumulated in cytosolic autophagosomes. In addition, inhibition of autophagy decreased recognition by EBNA1-specific CD4+ T cell clones. Thus, lysosomal processing after autophagy may contribute to MHC class II-restricted surveillance of long-lived endogenous antigens including nuclear proteins relevant to disease.
- Published
- 2005
- Full Text
- View/download PDF
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