Mullighan Charles G, Goorha Salil, Radtke Ina, Miller Christopher B, Coustan-Smith Elaine, Dalton James D, Girtman Kevin, Mathew Susan, Ma Jing, Pounds Stanley B, Su Xiaoping, Pui Ching-Hon, Relling Mary V, Evans William E, Shurtleff Sheila A, Downing James R
Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Nature. 2007 Apr 12;446(7137):758-64. doi: 10.1038/nature05690.
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.
染色体畸变是急性淋巴细胞白血病（ALL）的一个标志，但仅凭其自身并不能诱发白血病。为了确定协同致癌性病变，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例儿科ALL患者的白血病细胞进行了全基因组分析。我们的分析揭示，在40%的B祖细胞ALL病例中，编码B淋巴细胞发育和分化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点，在31.7%的病例中发生改变。所鉴定出的PAX5突变导致PAX5蛋白水平降低或产生亚效等位基因。在TCF3（也称为E2A）、EBF1、LEF1、IKZF1（IKAROS）和IKZF3（AIOLOS）中也检测到了缺失。这些发现表明，直接破坏控制B细胞发育和分化的信号通路有助于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中新分子病变方面的作用。
