Seto M, Jaeger U, Hockett R D, Graninger W, Bennett S, Goldman P, Korsmeyer S J
Department of Medicine, Howard Hughes Medical Institute, Washington University School of Medicine, St Louis, MO 63110.
EMBO J. 1988 Jan;7(1):123-31. doi: 10.1002/j.1460-2075.1988.tb02791.x.
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.
人类淋巴瘤中最常见的易位，即t(14;18)(q32;q21)，产生了异质性的4.2 - 7.2 kb Bcl-2免疫球蛋白（Ig）嵌合mRNA，这些mRNA由不同的Bcl-2 5'外显子和多样的Ig 3'非翻译区（UTR）产生。正常人类Bcl-2基因具有三个外显子结构，有一个非翻译的第一外显子、一个220 bp的选择性内含子I，但有一个巨大的370 kb内含子II。S1保护和引物延伸分析确定了外显子II中与经典启动子元件相关的起始位点以及一个与Ig可变区增强子同源的十聚体（ATG-CAAAGCA）。在富含GC且有Sp1结合基序的外显子I区域也发现了多个起始位点。大多数t(14;18)断点聚集在Bcl-2的3'UTR内，这表明该事件与基因失调有关。导入SU-DHL-6的Ig恒定区（Cγ）基因座的Bcl-2基因显示出体细胞突变。虽然Bcl-2-Ig mRNA的半衰期未改变，为2.5小时，但Bcl-2-Ig基因显示出成熟B细胞转录率过高。这表明易位的Bcl-2等位基因已逃脱正常的调控机制。
