ALTERNATIVE PROMOTERS AND EXONS, SOMATIC MUTATION AND DEREGULATION OF THE BCL-2-IG FUSION GENE IN LYMPHOMA
ALTERNATIVE PROMOTERS AND EXONS, SOMATIC MUTATION AND DEREGULATION OF THE BCL-2-IG FUSION GENE IN LYMPHOMA
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DOI：
10.1002/j.1460-2075.1988.tb02791.x
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发表时间：
1988-01-01
期刊：
影响因子：
11.4
通讯作者：
KORSMEYER, SJ
中科院分区：
文献类型：
--
作者：
SETO, M;JAEGER, U;KORSMEYER, SJ
人类淋巴瘤中最常见的易位是t(14;18)(q32;q21)，它产生异质的4.2-7.2 kb Bcl-2免疫球蛋白（Ig）嵌合mrna，由Bcl-2 5‘外显子和不同的Ig 3’非翻译区（UT）产生。正常人类Bcl-2基因具有三外显子结构，第一外显子为未翻译外显子，兼性内含子I为220 bp，内含子II为370 kb。S1保护和引物延伸分析确定了与经典启动子元件和与Ig可变区增强子同源的十核核苷酸（ATGCAAAGCA）相关的外显子II的起始位点。在1号外显子含有Sp1结合基序的富含gc的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”UT内，这表明该事件与基因解除调控有关。将Bcl-2基因导入到SU-DHL-6的Ig常数（C.gamma）位点后，出现体细胞突变。虽然Bcl-2-Ig mrna的半衰期为2.5小时，但Bcl-2-Ig基因在成熟b细胞中的转录率高得不合适。这表明易位的Bcl-2等位基因逃脱了正常的控制机制。
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 (ATGCAAAGCA) 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.