STRUCTURAL ORGANIZATION OF THE BCR GENE AND ITS ROLE IN THE PH' TRANSLOCATION
STRUCTURAL ORGANIZATION OF THE BCR GENE AND ITS ROLE IN THE PH' TRANSLOCATION
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DOI：
10.1038/315758a0
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发表时间：
1985-01-01
期刊：
影响因子：
64.8
通讯作者：
GROSVELD, G
中科院分区：
文献类型：
--
作者：
HEISTERKAMP, N;STAM, K;GROSVELD, G
费城 (Ph') 染色体是一条异常的 22 号染色体（参考文献 1），是与一种人类白血病——慢性粒细胞白血病 (CML) 密切相关的特定人类染色体异常的最著名例子之一。 9 号染色体上包含 c-ablonco 基因的一个小区域被易位至 22 号染色体，这一发现促使人们进行研究以阐明与这种疾病有关的分子机制。我们之前已经证明，一名 CML 患者的 9 号染色体包含最 5' v-abl 同源外显子 3 的 5' 14 KB 断点。这些数据表明c-ablin CML 的作用，这一理论得到CML 细胞系K562 中异常大小的dabl 信使RNA4,5 和蛋白6 的存在的支持。 22 号染色体上涉及易位的区域也已被确定：迄今为止检查的所有 Ph' 阳性患者在 5.8 kb 区域内都有一个断点，我们建议将其命名为“断点簇区域”(bcr)7。为了确定她是否含有蛋白质编码区域，对 bcr 的探针与互补 DNA 序列杂交的能力进行了测试。 0.6-kbHindIII/BamHlbcr 限制酶片段被证明适合从人成纤维细胞 cDNA 文库中分离多个 cDNA 克隆8。使用bcrcDNA序列，我们获得的数据强烈表明Ph'阳性CML患者的白血病细胞中存在嵌合bcr/ablmRNA。最近分离的含有 bcrandabl 序列的 cDNA 克隆证实了这一发现12。由于嵌合 mRNA 的 bcr 部分可能需要诱导人类 c-ablonco 基因的转化活性，因此我们现在已开始研究来表征正常的“bcr 基因”并确定其编码域内易位的影响。我们证明，由于 Ph' 易位，嵌合 bcr/ablmRNA 中包含了不同数量的 bcrexons。该 mRNA 中的 bcr 基因序列可能负责 abl 细胞原癌基因向癌基因的转变。
The Philadelphia (Ph′) chromosome, an abnormal chromosome 22 (ref. 1), is one of the best-known examples of a specific human chromosomal abnormality strongly associated with one form of human leukaemia, chronic myelocytic leukaemia (CML). The finding2that a small region of chromosome 9 which includes the c-abloncogene is translocated to chromosome 22 prompted studies to elucidate the molecular mechanisms involved in this disease. We have demonstrated previously that the chromosome 9 of one patient with CML contains a breakpoint 14 kilobases (kb) 5′ of the most 5′ v-abl-homologous exon3. These data suggest a role for c-ablin CML, a theory supported by the presence of an abnormally sizedablmessenger RNA4,5and protein6in the CML cell line K562. The region involved in the translocation on chromosome 22 has also been identified: all Ph′-positive patients examined to date have a breakpoint within a 5.8-kb region, for which we have proposed the name ‘breakpoint cluster region’ (bcr)7. To determine whether her contains protein-encoding regions, probes frombcrwere tested for their ability to hybridize to complementary DNA sequences. A 0.6-kbHindIII/BamHlbcrrestriction enzyme fragment proved suitable for isolating several cDNA clones from a human fibroblast cDNA library8. UsingbcrcDNA sequences, we obtained data strongly suggesting the presence of a chimaericbcr/ablmRNA in the leukaemic cells of Ph′-positive CML patients. The recent isolation of cDNA clones containingbcrandablsequences confirms this finding12. Because thebcrpart of the chimaeric mRNA could be required to induce the transforming activity of the human c-abloncogene, we have now initiated studies to characterize the normal ‘bcrgene’ and to determine the effect of a translocation within its coding domain. We demonstrate that as a result of the Ph′ translocation, a variable number ofbcrexons are included in the chimaericbcr/ablmRNA. Thebcrgene sequences in this mRNA could be responsible for the transition of theablcellular proto-oncogene into an oncogene.