Allele-specific activation of the c-myc gene in an atypical Burkitt's lymphoma carrying the t(2;8) chromosomal translocation 250 kb downstream from c-myc.
The genetic structure and regulation of the c-myc gene was comprehensively studied for the first time in Burkitt's lymphoma with t(2;8) translocation. In a Burkitt's lymphoma cell line, KOBK101, the immunoglobulin kappa-encoding gene on chromosome 2, accompanied by its enhancer, was translocated to the pvt-1 locus located about 250 kb downstream from c-myc on chromosome 8. Only the c-myc allele on the translocated chromosome carried aberrant SalI and KpnI sites in the first intron, so the two c-myc alleles and their transcripts were analyzed separately. The c-myc allele on the untranslocated chromosome conserved the normal c-myc sequence and was transcriptionally silent. In contrast, the c-myc allele on the translocated chromosome was actively transcribed at three- to fivefold higher levels, as compared with non-malignant B-cell lines. Additionally, it carried predominant multiple mutations consisting of 64 nucleotide substitutions, three short deletions, and a one-base insertion, most of which clustered in the first exon and intron. The 24-base deletion in the first intron completely overlapped the binding site of a putative negative transcriptional factor of the 138-kDa phosphoprotein, MIF. Thus, the multiple mutations and the deregulated, allele-specific expression of c-myc were associated with the chromosomal translocation in cis. Together activation by the long-distance immunoglobulin kappa enhancer, and the alleviation of negative regulation by the mutations, seemed to cause the allele-specific activation of c-myc.
Tachibana
K
K
Department of Microbiology, Keio University School of Medicine, Tokyo, Japan.
Takayama
N
N
Matsuo
K
K
Kato
S
S
Yamamoto
K
K
Ohyama
K
K
Umezawa
A
A
Takano
T
T
D000483:Alleles; D001483:Base Sequence; D015152:Blotting, Northern; D002051:Burkitt Lymphoma / Q000235:genetics*; D002889:Chromosomes, Human, Pair 2; D002898:Chromosomes, Human, Pair 8; D004273:DNA, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D015183:Restriction Mapping; D014158:Transcription, Genetic; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm