EBV transformation overrides gene expression patterns of B cell differentiation stages.
EBV-associated Hodgkin lymphoma (HL) and some post-transplant lymphoproliferative disease (PTLD) cases originate from pro-apoptotic germinal center (GC) B cells that have acquired destructive somatic Ig V gene mutations and were presumably rescued from apoptosis by EBV. To find out whether B cell receptor-crippled GC B cells acquire features of HL and/or PTLD cells upon EBV-infection and to reveal the impact of EBV on expression of B cell differentiation markers, we compared lymphoblastoid cell lines (LCLs) from GC B cells (including BCR-crippled GC-LCLs) to monoclonal LCLs from naïve B cells (N-LCLs). In addition, we analyzed the controversially discussed effect of EBV-infection on the GC B-cell-specific process of somatic hypermutation in vitro. Irrespective of their cellular origin, LCLs expressed CD20, CD30, CD38, AID, Pu.1, and with one exception Syk, but lacked expression of the GC B cell marker BCL-6. Interestingly, the T cell transcription factor GATA-3 that is aberrantly expressed in HL was induced in most GC-LCLs and the memory B cell marker CD27 was activated in N-LCLs. Remarkably, only 4 of 24 GC-LCLs showed significant somatic hypermutation activity, demonstrating that EBV usually silences hypermutation upon infection of GC B cells. Notably, one of three N-LCL showed a low level of intraclonal diversification. Thus, EBV-infection deregulates multiple differentiation factors and processes in B cells, leading to a largely homogenous phenotype of EBV-infected B cells in latency III.
Siemer
Dörte
D
University of Duisburg-Essen, Medical School, Institute for Cell Biology (Tumor Research), Virchowst. 173, 45122 Essen, Germany. doerte.siemer@uni-due.de
Kurth
Julia
J
Lang
Stephan
S
Lehnerdt
Götz
G
Stanelle
Jens
J
Küppers
Ralf
R
D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism / Q000821:virology*; D015415:Biomarkers; D015153:Blotting, Western; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral / Q000502:physiology*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain / Q000235:genetics; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006689:Hodgkin Disease / Q000276:immunology / Q000473:pathology / Q000821:virology; D006801:Humans; D010641:Phenotype; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics; D014763:Viral Matrix Proteins / Q000378:metabolism; D017735:Virus Latency
D015415:Biomarkers; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins