Miesfeldt S, Kim S, Hanson C A, Bohjanen P R, Leiden J M, Crist W M, Carroll A J, Thompson C B
Howard Hughes Medical Institute, Chicago, IL 60637.
Cancer Genet Cytogenet. 1993 Jul 1;68(1):34-41. doi: 10.1016/0165-4608(93)90071-s.
Chromosome translocations that disrupt or alter gene function have been implicated in the pathogenesis of a variety of malignancies. Therefore, identification of a translocation breakpoint has become a more important means by which to identify genes involved in cellular transformation. A common site of translocation in myeloid and lymphoid malignancies involves 11q23. One human protooncogene, ETS1, has been localized to this chromosomal segment, and several tumours with 11q23 translocations have been shown to have altered ETS1 DNA migration after restriction enzyme digestion. Two laboratories, however, have recently localized the 11q23 breakpoint region to a small region of DNA telomeric of the CD3 loci, a region at considerable distance from the ETS1 gene locus. Therefore, it is difficult to reconcile the studies that suggest altered migration of fragments associated with ETS1 and lack of a localization of the breakpoint to a region near the ETS1 gene. Recently, in our studies to characterize the promoter/enhancer region of the ETS1 protooncogene, we had the opportunity to analyze DNA from 18 patients with acute leukemia involving chromosome 11q23 aberrations. We were unable to demonstrate rearrangement of the ETS1 gene in this group, thus confirming that the 11q23 breakpoint does not involve ETS1 protooncogene. In one patient, however, a DNA break in the region of the ETS1 promoter was detected reproducibly. This DNA break was mapped to the major DNaseI hypersensitive site in the ETS1 promoter. Mapping from both sides of the break demonstrated that the break must have occurred during processing of the leukemic cells for DNA analysis. Therefore, artifactual DNA breaks can occur at nuclease-hypersensitive sites of active genes. These data suggest that previous reports of chromosomal translocations involving the ETS1 protooncogene may have resulted from DNA breaks at nuclease hypersensitive sites. This mechanism may account for sporadic case reports of altered restriction enzyme fragment migration involving genes that are not ultimately shown to be associated with the chromosome translocation being examined.
破坏或改变基因功能的染色体易位与多种恶性肿瘤的发病机制有关。因此，识别易位断点已成为鉴定参与细胞转化的基因的更重要手段。髓系和淋巴系恶性肿瘤中常见的易位位点涉及11q23。一种人类原癌基因ETS1已定位到该染色体区段，并且已显示几种具有11q23易位的肿瘤在限制性内切酶消化后具有改变的ETS1 DNA迁移。然而，两个实验室最近将11q23断点区域定位到CD3基因座端粒的一小段DNA区域，该区域与ETS1基因座相距甚远。因此，很难协调那些表明与ETS1相关的片段迁移改变以及断点未定位到ETS1基因附近区域的研究。最近，在我们表征ETS1原癌基因启动子/增强子区域的研究中，我们有机会分析了18例涉及11号染色体q23畸变的急性白血病患者的DNA。我们未能在该组中证明ETS1基因的重排，从而证实11q23断点不涉及ETS1原癌基因。然而，在一名患者中，可重复检测到ETS1启动子区域的DNA断裂。该DNA断裂定位于ETS1启动子中的主要DNaseI超敏位点。从断裂两侧进行定位表明，该断裂一定发生在白血病细胞用于DNA分析的处理过程中。因此，人工DNA断裂可发生在活性基因的核酸酶超敏位点。这些数据表明，先前关于涉及ETS1原癌基因的染色体易位的报道可能是由核酸酶超敏位点的DNA断裂引起的。这种机制可能解释了关于改变的限制性酶切片段迁移的散发病例报告，这些报告涉及最终未显示与所检测的染色体易位相关的基因。
