Strout M P, Marcucci G, Bloomfield C D, Caligiuri M A
Division of Hematology-Oncology, Department of Internal Medicine, Comprehensive Cancer Center at The Ohio State University, 320 West 10th Avenue, Columbus, OH 43210, USA.
Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2390-5. doi: 10.1073/pnas.95.5.2390.
Chromosome abnormalities resulting in gene fusions are commonly associated with acute myeloid leukemia (AML), however, the molecular mechanism(s) responsible for these defects are not well understood. The partial tandem duplication of the ALL1 (MLL) gene is found in patients with AML and trisomy 11 as a sole cytogenetic abnormality and in 11% of patients with AML and normal cytogenetics. This defect results from the genomic fusion of ALL1 intron 6 or intron 8 to ALL1 intron 1. Here, we examined the DNA sequence at the genomic fusion in nine cases of AML with a tandem duplication of ALL1 spanning exons 2-6. Each breakpoint occurred within intron 6 of the ALL1 breakpoint cluster region and within a discrete 3.8-kb region near the 3' end of intron 1. In seven cases, a distinct point of fusion of intron 6 with intron 1 could not be identified. Instead, the sequence gradually diverged from an Alu element in intron 6 to an Alu element in intron 1 through a heteroduplex fusion. Thus, these rearrangements appear to be the result of a recombination event between homologous Alu sequences in introns 6 and 1. In two cases, the genomic junction was distinct and involved the fusion of a portion of an Alu element in intron 6 with non-Alu sequence in intron 1. These data support the hypothesis that a recombination event between homologous Alu sequences is responsible for the partial tandem duplication of ALL1 in the majority of AML cases with this genetic defect. Although Alu element-mediated homologous recombination events in germline cells are thought to be responsible for partial gene duplications or deletions in many inherited diseases, this appears to be the first demonstration identifying Alu element-mediated recombination as a consistent mechanism for gene rearrangement in somatic tissue.
导致基因融合的染色体异常通常与急性髓系白血病（AML）相关，然而，造成这些缺陷的分子机制尚未完全明确。在AML患者中发现了ALL1（MLL）基因的部分串联重复，且11号三体是唯一的细胞遗传学异常，在11%的AML且细胞遗传学正常的患者中也存在这种情况。这种缺陷是由ALL1内含子6或内含子8与ALL1内含子1的基因组融合导致的。在此，我们检测了9例ALL1外显子2 - 6存在串联重复的AML病例中基因组融合处的DNA序列。每个断点都出现在ALL1断点簇区域的内含子6内以及内含子1 3'端附近一个离散的3.8 kb区域内。在7例病例中，无法确定内含子6与内含子1的明显融合点。相反，序列通过异源双链融合从内含子6中的一个Alu元件逐渐分歧到内含子1中的一个Alu元件。因此，这些重排似乎是内含子6和1中同源Alu序列之间重组事件的结果。在2例病例中，基因组连接是明显的，涉及内含子6中一部分Alu元件与内含子1中非Alu序列的融合。这些数据支持了这样的假设，即同源Alu序列之间的重组事件是大多数具有这种遗传缺陷的AML病例中ALL1部分串联重复的原因。尽管种系细胞中Alu元件介导的同源重组事件被认为是许多遗传性疾病中部分基因重复或缺失的原因，但这似乎是首次证明Alu元件介导的重组是体细胞组织中基因重排的一种一致机制。
