Identification of a locus control region in the immunoglobulin heavy-chain locus that deregulates c-myc expression in plasmacytoma and Burkitt's lymphoma cells.
In murine plasmacytoma and human Burkitt's lymphoma cells, one allele of c-myc is translocated into one of the immunoglobulin loci, resulting in a characteristic pattern of deregulated c-myc transcription. Translocation events between c-myc and the IgH locus segregate c-myc and the IgH intron enhancer to different reciprocal products in all plasmacytomas and in most Burkitt's lymphoma cells, suggesting that an additional element(s) capable of affecting c-myc expression over a large and variable distance must exist in the IgH locus. The region 3' of the IgH C alpha gene contains four tissue-specific and cell stage-specific DNase I hypersensitive sites (HSs), two of which map to the late B cell-specific 3' C alpha enhancer. We report here that DNA sequences comprising the two other 3' C alpha HSs contain potential protein-binding motifs for trans-activators commonly associated with immunoglobulin enhancers and that these sites can function as cell stage-specific enhancers in transient B cell assays. A DNA fragment containing all four HSs (HS1234) synergistically activates c-myc transcription in plasmacytoma and Burkitt's lymphoma cells in transient assays and induces high-level transcription, a promoter shift from P2 to P1, and an increase in readthrough transcription in stable transfections. Furthermore, plasmacytoma clones stably transfected with a HS1234-linked c-myc construct express c-myc in a position-independent, copy number-dependent manner. These results suggest that HS1234 may function as a locus control region (LCR), deregulating c-myc expression in t(15;12) plasmacytomas, as well as potentially contributing to aspects of normal IgH chain expression.
Hutchinson Cancer Center, University of Washington School of Medicine, Seattle 98104.
L
L
Madisen
M
M
Groudine
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D001483:Base Sequence; D002051:Burkitt Lymphoma / Q000235:genetics* / Q000276:immunology; D002874:Chromosome Mapping; D004273:DNA, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005803:Genes, Immunoglobulin; D005809:Genes, Regulator; D016259:Genes, myc; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D010954:Plasmacytoma / Q000235:genetics* / Q000276:immunology; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D013045:Species Specificity; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured / Q000276:immunology
D004273:DNA, Neoplasm; D007143:Immunoglobulin Heavy Chains; D012319:RNA Polymerase II