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Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia

机译：全基因组急性淋巴细胞白血病遗传变异的分析

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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 PAXS gene was the most frequent target of somatic mutation, being altered in 31.7% of cases. The identified PAXS 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.
机译：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。为了鉴定合作的致癌性病变，我们使用高分辨率的单核苷酸多态性阵列和基因组DNA测序技术对242名小儿ALL患者的白血病细胞进行了全基因组分析。我们的分析揭示了在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的缺失，扩增，点突变和结构重排。 PAXS基因是体细胞突变的最常见靶标，在31.7％的病例中被改变。鉴定出的PAXS突变导致PAX5蛋白水平降低或产生亚型等位基因。在TCF3（也称为E2A），EBF1，LEF1，IKZF1（IKAROS）和IKZF3（AIOLOS）中也检测到缺失。这些发现表明，直接破坏控制B细胞发育和分化的途径有助于B祖细胞ALL的发病机理。而且，这些数据证明了高分辨率的全基因组方法能够识别癌症中的新分子损伤。

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