Heisterkamp N, Stam K, Groffen J, de Klein A, Grosveld G
Nature. 1985;315(6022):758-61. doi: 10.1038/315758a0.
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 finding that a small region of chromosome 9 which includes the c-abl oncogene 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 exon. These data suggest a role for c-abl in CML, a theory supported by the presence of an abnormally sized abl messenger RNA and protein in 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). To determine whether bcr contains protein-encoding regions, probes from bcr were tested for their ability to hybridize to complementary DNA sequences. A 0.6-kb HindIII/BamHI bcr restriction enzyme fragment proved suitable for isolating several cDNA clones from a human fibroblast cDNA library. Using bcr cDNA sequences, we obtained data strongly suggesting the presence of a chimaeric bcr/abl mRNA in the leukaemic cells of Ph'-positive CML patients. The recent isolation of cDNA clones containing bcr and abl sequences confirms this finding. Because the bcr part of the chimaeric mRNA could be required to induce the transforming activity of the human c-abl oncogene, we have now initiated studies to characterize the normal 'bcr gene' 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 of bcr exons are included in the chimaeric bcr/abl mRNA. The bcr gene sequences in this mRNA could be responsible for the transition of the abl cellular proto-oncogene into an oncogene.
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-abl原癌基因的一个小区域易位至22号染色体这一发现，促使人们开展研究以阐明该疾病所涉及的分子机制。我们之前已经证明，一名慢性粒细胞白血病患者的9号染色体在最5'端的v-abl同源外显子5'端14千碱基（kb）处存在一个断点。这些数据表明c-abl在慢性粒细胞白血病中发挥作用，这一理论得到了慢性粒细胞白血病细胞系K562中存在异常大小的abl信使RNA和蛋白质的支持。22号染色体上参与易位的区域也已确定：迄今为止检测的所有Ph'阳性患者在一个5.8 kb区域内都有一个断点，我们将其命名为“断点簇区域”（bcr）。为了确定bcr是否包含蛋白质编码区域，对来自bcr的探针与互补DNA序列杂交的能力进行了检测。一个0.6 kb的HindIII/BamHI bcr限制性酶切片段被证明适合从人成纤维细胞cDNA文库中分离出几个cDNA克隆。利用bcr cDNA序列，我们获得的数据有力地表明，Ph'阳性慢性粒细胞白血病患者的白血病细胞中存在一种嵌合的bcr/abl mRNA。最近分离出的包含bcr和abl序列的cDNA克隆证实了这一发现。由于嵌合mRNA的bcr部分可能是诱导人类c-abl原癌基因转化活性所必需的，我们现在已开始研究以表征正常的“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，可变数量的bcr外显子被包含在嵌合的bcr/abl mRNA中。该mRNA中的bcr基因序列可能是导致abl细胞原癌基因转变为癌基因的原因。
