C-myc activation impairs the NF-kappaB and the interferon response: implications for the pathogenesis of Burkitt's lymphoma.
Deregulation of the proto-oncogene c-myc is a key event in the pathogenesis of many tumors. A paradigm is the activation of the c-myc gene by chromosomal translocations in Burkitt lymphoma (BL). Despite expression of a restricted set of Epstein-Barr viral (EBV) antigens, BL cells are not recognized by antigen-specific cytotoxic T cells (CTLs) because of their inability to process and present HLA class I-restricted antigens. In contrast, cells of EBV-driven posttransplant lymphoproliferative disease (PTLD) are recognized and rejected by EBV-specific CTLs. It is not known whether the poor immunogenicity of BL cells is due to nonexpression of viral antigens, overexpression of c-myc, or both. To understand the basis for immune recognition and escape, we have compared the mRNA expression profiles of BL and EBV-immortalized cells (as PTLD model). Among the genes expressed at low level in BL cells, we have identified many genes involved in the NF-kappaB and interferon response that play a pivotal role in antigen presentation and immune recognition. Using a cell line in which EBNA2 and c-myc can be regulated at will, we show that c-MYC negatively regulates STAT1, the central player linking the Type-I and Type-II interferon response. Switching off c-myc expression leads to STAT1 induction through a direct and indirect mechanism involving induction of Type-I interferons. c-MYC thus masks an interferon-inducing activity in these cells. Our findings imply that immune escape of tumor cells is not only a matter of in vivo selection but may be additionally promoted by activation of a cellular oncogene.
Schlee
Martin
M
Institute of Clinical Molecular Biology and Tumor Genetics, GSF-National Research Center for Environment and Health, München, Germany.
Hölzel
Michael
M
Bernard
Sandra
S
Mailhammer
Reinhard
R
Schuhmacher
Marino
M
Reschke
Judith
J
Eick
Dirk
D
Marinkovic
Dragan
D
Wirth
Thomas
T
Rosenwald
Andreas
A
Staudt
Louis M
LM
Eilers
Martin
M
Baran-Marszak
Fanny
F
Fagard
Remi
R
Feuillard
Jean
J
Laux
Gerhard
G
Bornkamm
Georg W
GW
D015153:Blotting, Western; D002051:Burkitt Lymphoma / Q000209:etiology*; D047369:Chromatin Immunoprecipitation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D016259:Genes, myc / Q000502:physiology*; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology*; D046228:Microarray Analysis; D016328:NF-kappa B / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
C000715470:MAS1 protein, human; D016328:NF-kappa B; D009363:Neoplasm Proteins; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D016899:Interferon-beta