The partial tandem duplication of ALL1 (MLL) is consistently generated by Alu-mediated homologous recombination in acute myeloid leukemia
The partial tandem duplication of ALL1 (MLL) is consistently generated by Alu-mediated homologous recombination in acute myeloid leukemia
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DOI：
10.1073/pnas.95.5.2390
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发表时间：
1998-03-03
影响因子：
11.1
通讯作者：
Caligiuri, MA
中科院分区：
文献类型：
--
作者：
Strout, MP;Marcucci, G;Caligiuri, MA
导致基因融合的染色体异常通常与急性髓性白血病 (AML) 相关，然而，导致这些缺陷的分子机制尚不清楚。在 AML 和 11 三体性患者中发现 ALL1 (MLL) 基因的部分串联重复，这是一种唯一的细胞遗传学异常，在 AML 和细胞遗传学正常的患者中，有 11% 存在这种情况。这种缺陷是由于 ALL1 内含子 6 或内含子 8 与 ALL1 内含子 1 的基因组融合所致。在这里，我们检查了 9 例 AML 病例中基因组融合处的 DNA 序列，其中 ALL1 跨越外显子 2-6 的串联重复。每个断点均发生在 ALL1 断点簇区域的内含子 6 内以及内含子 1 3' 端附近的离散 3.8-kb 区域内，在七种情况下，无法识别内含子 6 与内含子 1 的独特融合点，相反，序列通过异源双链体融合逐渐从内含子 6 中的 Alu 元件分化为内含子 1 中的 Alu 元件，因此，这些重排似乎是重组的结果内含子 6 和 1 中同源 Alu 序列之间的事件，在两种情况下，基因组连接是不同的，涉及内含子 6 中 Alu 元件的一部分与内含子 1 中非 Alu 序列的融合，这些数据支持以下假设：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 部分串联复制的原因，尽管认为种系细胞中 Alu 元件介导的同源重组事件由于 Alu 元件导致许多遗传性疾病中的部分基因重复或缺失，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致机制。
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.