Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia
Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia
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DOI：
10.1038/nature05690
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发表时间：
2007-04-12
期刊：
影响因子：
64.8
通讯作者：
Downing, James R.
中科院分区：
文献类型：
--
作者：
Mullighan, Charles G.;Goorha, Salil;Downing, James R.
染色体畸变是急性淋巴细胞白血病（ALL）的标志，但单独不能诱发白血病。为了确定协同致癌病变，我们使用高分辨率单核苷酸多态性阵列和基因组DNA测序对242例儿童ALL患者的白血病细胞进行了全基因组分析。我们的分析显示，在40%的B祖细胞ALL病例中，编码B淋巴细胞发育和分化的主要调节因子的基因存在缺失、扩增、点突变和结构重排。PAX5基因是体细胞突变最常见的靶基因，在31.7%的病例中发生了改变。鉴定的PAX5突变导致PAX5蛋白水平降低或产生亚纯型等位基因。在TCF 3（也称为E2A）、EBF 1、LEF 1、IKZF 1（IKAROS）和IKZF 3（AIOLOS）中也检测到缺失。这些发现表明，控制B细胞发育和分化的通路的直接破坏有助于B祖细胞ALL的发病机制。此外，这些数据证明了高分辨率、全基因组方法在识别癌症新分子病变方面的能力。
Chromosomal aberrations are a hallmark of acute lymphoblastic leukaemia ( ALL) but alone fail to induce leukaemia. To identify cooperating oncogenic lesions, we performed a genome-wide analysis of leukaemic cells from 242 paediatric ALL patients using high-resolution, single-nucleotide polymorphism arrays and genomic DNA sequencing. Our analyses revealed deletion, amplification, point mutation and structural rearrangement in genes encoding principal regulators of B lymphocyte development and differentiation in 40% of B-progenitor ALL cases. The PAX5 gene was the most frequent target of somatic mutation, being altered in 31.7% of cases. The identified PAX5 mutations resulted in reduced levels of PAX5 protein or the generation of hypomorphic alleles. Deletions were also detected in TCF3 ( also known as E2A), EBF1, LEF1, IKZF1 (IKAROS) and IKZF3 (AIOLOS). These findings suggest that direct disruption of pathways controlling B-cell development and differentiation contributes to B-progenitor ALL pathogenesis. Moreover, these data demonstrate the power of high-resolution, genome-wide approaches to identify new molecular lesions in cancer.