EBNA3B-deficient EBV promotes B cell lymphomagenesis in humanized mice and is found in human tumors
| Autor: | Cliona M. Rooney, Patrick C. Rämer, Christian Münz, Jaap M. Middeldorp, Fathima Zumla Cader, John G. Gribben, Martin J. Allday, Barbara Savoldo, Rita Coutinho, Paul Murray, Jamie P. Nourse, Sonja Meixlsperger, Laurie Pinaud, Hazem A. H. Ibrahim, Robert E. White, Csaba Bödör, Maher K. Gandhi, Mark Bower, Kikkeri N. Naresh |
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| Přispěvatelé: | University of Zurich, Münz, Christian, Pathology, CCA - Oncogenesis |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Epstein-Barr Virus Infections
Herpesvirus 4 Human Genes Viral DNA Mutational Analysis Mice SCID 2700 General Medicine 10263 Institute of Experimental Immunology medicine.disease_cause Mice Postoperative Complications Mice Inbred NOD hemic and lymphatic diseases Genes Tumor Suppressor Cell Line Transformed Mice Knockout education.field_of_study Hematopoietic Stem Cell Transplantation General Medicine medicine.anatomical_structure Research Article Lymphoma B-Cell T cell Transplantation Heterologous Population 610 Medicine & health Biology Interferon-gamma Immune system Antigen medicine Animals Humans education B cell Chimera Tumor Suppressor Proteins Cell Transformation Viral medicine.disease Virology Epstein–Barr virus Lymphoproliferative Disorders Lymphoma Chemokine CXCL10 Tumor Virus Infections Epstein-Barr Virus Nuclear Antigens Mutation Cancer research 570 Life sciences biology Diffuse large B-cell lymphoma Gene Deletion |
| Zdroj: | Journal of Clinical Investigation, 122(4), 1487-1502. The American Society for Clinical Investigation White, R E, Raemer, P C, Naresh, K N, Meixlsperger, S, Pinaud, L, Rooney, C, Savoldo, B, Coutinho, R, Bodor, C, Gribben, J, Ibrahim, H A, Bower, M, Nourse, J P, Gandhi, M K, Middeldorp, J M, Cader, F Z, Murray, P, Munz, C & Allday, M J 2012, ' EBNA3B-deficient EBV promotes B cell lymphomagenesis in humanized mice and is found in human tumors ', Journal of Clinical Investigation, vol. 122, no. 4, pp. 1487-1502 . https://doi.org/10.1172/JCI58092 |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/JCI58092 |
| Popis: | Epstein-Barr virus (EBV) persistently infects more than 90% of the human population and is etiologically linked to several B cell malignancies, including Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and diffuse large B cell lymphoma (DLBCL). Despite its growth transforming properties, most immune-competent individuals control EBV infection throughout their lives. EBV encodes various oncogenes, and of the 6 latency-associated EBV-encoded nuclear antigens, only EBNA3B is completely dispensable for B cell transformation in vitro. Here, we report that infection with EBV lacking EBNA3B leads to aggressive, immune-evading monomorphic DLBCL-like tumors in NOD/SCID/γc–/– mice with reconstituted human immune system components. Infection with EBNA3B-knockout EBV (EBNA3BKO) induced expansion of EBV-specific T cells that failed to infiltrate the tumors. EBNA3BKO-infected B cells expanded more rapidly and secreted less T cell–chemoattractant CXCL10, reducing T cell recruitment in vitro and T cell–mediated killing in vivo. B cell lines from 2 EBV-positive human lymphomas encoding truncated EBNA3B exhibited gene expression profiles and phenotypic characteristics similar to those of tumor-derived lines from the humanized mice, including reduced CXCL10 secretion. Screening EBV-positive DLBCL, HL, and BL human samples identified additional EBNA3B mutations. Thus, EBNA3B is a virus-encoded tumor suppressor whose inactivation promotes immune evasion and virus-driven lymphomagenesis. |
| Databáze: | OpenAIRE |
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