c-Myc and Rel/NF-kappaB are the two master transcriptional systems activated in the latency III program of Epstein-Barr virus-immortalized B cells.
The Epstein-Barr virus (EBV) latency III program imposed by EBNA2 and LMP1 is directly responsible for immortalization of B cells in vitro and is thought to mediate most immunodeficiency-related posttransplant lymphoproliferative diseases in vivo. To answer the question whether and how this proliferation program is related to c-Myc, we have established the transcriptome of both c-Myc and EBV latency III proliferation programs using a Lymphochip specialized microarray. In addition to EBV-positive latency I Burkitt lymphoma lines and lymphoblastoid cell lines (LCLs), we used an LCL expressing an estrogen-regulatable EBNA2 fusion protein (EREB2-5) and derivative B-cell lines expressing a constitutively active or tetracycline-regulatable c-myc gene. A total of 897 genes were found to be fourfold or more up- or downregulated in either one or both proliferation programs compared to the expression profile of resting EREB2-5 cells. A total of 661 (74%) of these were regulated similarly in both programs. Numerous repressed genes were known targets of STAT1, and most induced genes were known to be upregulated by c-Myc and to be involved in cell proliferation. In keeping with the gene expression patterns, inactivation of c-Myc by a chemical inhibitor or by conditional expression of dominant-negative c-Myc and Max mutants led to proliferation arrest of LCLs. Most genes differently regulated in both proliferation programs corresponded to genes induced by NF-kappaB in LCLs, and many of them coded for immunoregulatory and/or antiapoptotic molecules. Thus, c-Myc and NF-kappaB are the two main transcription factors responsible for the phenotype, growth pattern, and biological properties of cells driven into proliferation by EBV.
Faumont
Nathalie
N
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6101, Centre Hospitalier Universitaire Dupuytren, Université de Limoges, Laboratoire d'Hématologie, 87025 Limoges, France.
Durand-Panteix
Stéphanie
S
Schlee
Martin
M
Grömminger
Sebastian
S
Schuhmacher
Marino
M
Hölzel
Michael
M
Laux
Gerhard
G
Mailhammer
Reinhard
R
Rosenwald
Andreas
A
Staudt
Louis M
LM
Bornkamm
Georg W
GW
Feuillard
Jean
J
D001402:B-Lymphocytes / Q000378:metabolism / Q000821:virology*; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002472:Cell Transformation, Viral; D016000:Cluster Analysis; D004247:DNA / Q000096:biosynthesis; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000378:metabolism; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D004854:Herpesvirus 4, Human / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D017735:Virus Latency
D019309:Epstein-Barr Virus Nuclear Antigens; D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D004247:DNA