Concomitant downregulation of IgH 3' enhancer activity and c-myc expression in a plasmacytoma x fibroblast environment: implications for dysregulation of translocated c-myc.
Regulation of immunoglobulin heavy chain (IgH) gene expression is controlled by a B cell-specific promoter, intronic enhancer and additional B cell-specific enhancer elements identified recently in the 3' end of the IgH locus. One of the latter elements, the IgH 3' enhancer, is of particular interest: (1) it is B cell-specific and active only in late B cell development; (2) in rodent plasmacytomas and in some human Burkitt's lymphomas it is part of a locus control region (LCR) that is involved in deregulation of the c-myc oncogene as a result of translocation into the IgH locus; and (3) it has been implicated in the mechanisms that control Ig gene class switch recombination. We have used a somatic cell hybridization approach to genetically analyse regulation of the activity of the IgH 3' enhancer. When mouse MPC11 plasmacytoma cells, in which the IgH 3' enhancer is active, are fused with fibroblasts, Ig expression is extinguished at the level of transcription. Here we show that in a MPC11 plasmacytoma x fibroblast environment, the IgH 3' enhancer is transcriptionally inactive. Furthermore, we demonstrate that binding of several B cell-specific transcription factors, essential for IgH 3' enhancer activity, is lacking, which may explain 3' enhancer inactivity, although the binding of repressors cannot be excluded. Moreover, the high expression level of c-myc, characteristic of the parental MPC11 cells carrying the t(12;15) translocation, is down-regulated in the hybrids to that in unfused fibroblasts. Therefore, inactivation of the IgH 3' enhancer is a multifactorial process affecting several transcription factors that control the cell-specific and developmental activity of the enhancer.
Thøger Andersen
A S
AS
Institute of Human Genetics, University of Aarhus, Denmark.
Jensen
A W
AW
Grant
P
P
Arulampalam
V
V
Pettersson
S
S
Junker
S
S
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001665:Binding Sites; D015536:Down-Regulation; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D016259:Genes, myc / Q000235:genetics*; D006801:Humans; D006822:Hybrid Cells / Q000378:metabolism*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007145:Immunoglobulin kappa-Chains / Q000235:genetics; D051379:Mice; D010954:Plasmacytoma / Q000235:genetics*; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism; D014178:Translocation, Genetic / Q000235:genetics*; D014407:Tumor Cells, Cultured
D007143:Immunoglobulin Heavy Chains; D007145:Immunoglobulin kappa-Chains; D014157:Transcription Factors