title: EBNA3B-deficient EBV promotes B cell lymphomagenesis in humanized mice and is found in human tumors.
abstract: 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.
authors.affiliation: Section of Virology, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Robert E
authors.initials: RE
authors.lastname: White
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Rämer
authors.forename: Kikkeri N
authors.initials: KN
authors.lastname: Naresh
authors.forename: Sonja
authors.initials: S
authors.lastname: Meixlsperger
authors.forename: Laurie
authors.initials: L
authors.lastname: Pinaud
authors.forename: Cliona
authors.initials: C
authors.lastname: Rooney
authors.forename: Barbara
authors.initials: B
authors.lastname: Savoldo
authors.forename: Rita
authors.initials: R
authors.lastname: Coutinho
authors.forename: Csaba
authors.initials: C
authors.lastname: Bödör
authors.forename: John
authors.initials: J
authors.lastname: Gribben
authors.forename: Hazem A
authors.initials: HA
authors.lastname: Ibrahim
authors.forename: Mark
authors.initials: M
authors.lastname: Bower
authors.forename: Jamie P
authors.initials: JP
authors.lastname: Nourse
authors.forename: Maher K
authors.initials: MK
authors.lastname: Gandhi
authors.forename: Jaap
authors.initials: J
authors.lastname: Middeldorp
authors.forename: Fathima Z
authors.initials: FZ
authors.lastname: Cader
authors.forename: Paul
authors.initials: P
authors.lastname: Murray
authors.forename: Christian
authors.initials: C
authors.lastname: Münz
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Allday
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed / Q000637:transplantation / Q000821:virology; D002472:Cell Transformation, Viral / Q000235:genetics*; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D002678:Chimera; D004252:DNA Mutational Analysis; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000821:virology*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D005814:Genes, Viral; D018380:Hematopoietic Stem Cell Transplantation; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000821:virology*; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000821:virology*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009154:Mutation; D011183:Postoperative Complications / Q000235:genetics / Q000821:virology*; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D014412:Tumor Virus Infections / Q000235:genetics / Q000821:virology*
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; C422762:EBNA-3B antigen; D019309:Epstein-Barr Virus Nuclear Antigens; D025521:Tumor Suppressor Proteins; D007371:Interferon-gamma