Acute myeloid leukemia with complex karyotypes and abnormal chromosome 21:: Amplification discloses overexpression of APP, ETS2, and ERG genes
Acute myeloid leukemia with complex karyotypes and abnormal chromosome 21:: Amplification discloses overexpression of APP, ETS2, and ERG genes
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DOI：
10.1073/pnas.0400272101
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发表时间：
2004-03-16
影响因子：
11.1
通讯作者：
de la Chapelle, A
中科院分区：
文献类型：
--
作者：
Baldus, CD;Liyanarachchi, S;de la Chapelle, A
通过研究参与简单重排（包括平衡易位和倒位）的基因，已经成功阐明了白血病发生的分子机制。相比之下，人们对复杂核型异常中改变的基因知之甚少。我们研究了具有复杂核型和异常 21 号染色体的急性髓性白血病 (AML) 患者。基于高分辨率细菌人工染色体 (BAC) 阵列的比较基因组杂交揭示了扩增主要发生在包含 APP 基因 (26.3 MB) 的 25 至 30 兆碱基 (MB) 区域以及位于 38.7-39.1 MB 的位置。 含有转录因子 ERG 和 ETS2。使用寡核苷酸阵列，与具有正常细胞遗传学的 AMI 对照组相比，APP 是迄今为止最过度表达的基因（平均倍数变化 19.74，P = 0.0003）； ERG 和 ETS2 也位列表达最高的 21 号染色体基因之列。 APP 和 ETS2 的过度表达与基因组扩增相关，但高 APP 表达甚至出现在细胞遗传学正常的 AML 患者亚群中（64 名患者中的 10 名，16%）。 APP 编码一种功能未知的糖蛋白，以前与阿尔茨海默病有关，但与 AML 无关。我们假设 APP 以及转录因子 ERG 和 ETS2 被涉及白血病发生的未知分子机制改变。我们的结果强调了分子解剖具有复杂核型的白血病细胞的价值。
Molecular mechanisms of leukemogenesis have been successfully unraveled by studying genes involved in simple rearrangements including balanced translocations and inversions. In contrast, little is known about genes altered in complex karyotypic abnormalities. We studied acute myeloid leukemia (AML) patients with complex karyotypes and abnormal chromosome 21. High-resolution bacterial artificial chromosome (BAC) array-based comparative genomic hybridization disclosed amplification predominantly in the 25- to 30-megabase (MB) region that harbors the APP gene (26.3 MB) and at position 38.7-39.1 MB that harbors the transcription factors ERG and ETS2. Using oligonucleotide arrays, APP was by far the most overexpressed gene (mean fold change 19.74, P = 0.0003) compared to a control group of AMI-with normal cytogenetics; ERG and ETS2 also ranked among the most highly expressed chromosome 21 genes. Overexpression of APP and ETS2 correlated with genomic amplification, but high APP expression occurred even in a subset of AML patients with normal cytogenetics (10 of 64, 16%). APP encodes a glycoprotein of unknown function previously implicated in Alzheimer's disease, but not in AML. We hypothesize that APP and the transcription factors ERG and ETS2 are altered by yet unknown molecular mechanisms involved in leukemogenesis. Our results highlight the value of molecularly dissecting leukemic cells with complex karyotypes.