Alternative promoters and exons, somatic mutation and deregulation of the Bcl-2-Ig fusion gene in lymphoma.
The most common translocation in human lymphoma, the t(14;18)(q32;q21), generates heterogeneous 4.2-7.2 kb Bcl-2-immunoglobulin (Ig) chimeric mRNAs resulting from alternative Bcl-2 5' exons and varied Ig 3' untranslated regions (UT). The normal human Bcl-2 gene has a three exon structure with an untranslated first exon, a facultative 220 bp intron I, but an enormous 370 kb intron II. S1 protection and primer extension analysis defined initiation sites in exon II associated with classic promoter elements and a decanucleotide (ATG-CAAAGCA) homologous with Ig variable region enhancers. Multiple initiation sites were also found in a GC-rich region with Sp1 binding motifs in exon I. Most t(14;18) breakpoints cluster within the 3' UT of Bcl-2 implicating that event in gene deregulation. The Bcl-2 gene introduced into the Ig constant (C gamma) locus of SU-DHL-6 displayed somatic mutation. While Bcl-2--Ig mRNAs demonstrated an unaltered 2.5 h half-life, the Bcl-2--Ig gene revealed an inappropriately high rate of transcription for a mature B-cell. This indicates the translocated Bcl-2 allele has escaped normal control mechanisms.
Seto
M
M
Department of Medicine, Howard Hughes Medical Institute, Washington University School of Medicine, St Louis, MO 63110.
Jaeger
U
U
Hockett
R D
RD
Graninger
W
W
Bennett
S
S
Goldman
P
P
Korsmeyer
S J
SJ
D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D004262:DNA Restriction Enzymes; D004273:DNA, Neoplasm / Q000235:genetics; D005091:Exons; D005803:Genes, Immunoglobulin; D005809:Genes, Regulator; D006801:Humans; D008223:Lymphoma / Q000235:genetics / Q000276:immunology*; D008969:Molecular Sequence Data; D009154:Mutation; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic
D004273:DNA, Neoplasm; D004262:DNA Restriction Enzymes