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Nature:利用SNP微阵列识别白血病有关的基因病灶

来源:科学时报 2007-04-16 08:41

    基因病灶利用SNP微阵列在整个基因组范围内对DNA版本数异常进行高分辨率分析的方法,被用来识别与儿童最常见的癌症——急性淋巴细胞性白血病有关的基因病灶。对来自242位患者的白血病母细胞所作的分析显示,在40%的B-先祖细胞急性淋巴细胞性白血病病例中,为B-淋巴细胞发育的关键调控因子编码的基因发生删除、放大、点突变和结构重排等问题。PAX5是最常见的目标。所获得的数据表明,能够绕开这些基因病灶所造成障碍的小分子细胞分化诱导因子可以作为研究新的治疗方法的一个重点,并且更具有普遍意义的是,它们展示了人们所熟悉的整个基因组范围内进行分析的方法作为识别癌症中新的小分子病灶的一种手段所具有的潜力。封面图片所示为白血病细胞的荧光原位杂交,它显示了9p13染色体上的PAX5向18q11.2位置上的ZNF521的融合。

部分英文原文:

Article

Nature 446, 758-764 (12 April 2007) | doi:10.1038/nature05690; Received 7 November 2006; Accepted 20 February 2007; Published online 7 March 2007

Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia

Charles G. Mullighan1,6, Salil Goorha1,6, Ina Radtke1, Christopher B. Miller1, Elaine Coustan-Smith2, James D. Dalton1, Kevin Girtman1, Susan Mathew1,7, Jing Ma5, Stanley B. Pounds3, Xiaoping Su5, Ching-Hon Pui2, Mary V. Relling4, William E. Evans4, Sheila A. Shurtleff1 & James R. Downing1

  1. Departments of Pathology,
  2. Oncology,
  3. Biostatistics,
  4. Pharmaceutical Sciences, and the
  5. Hartwell Center for Bioinformatics and Biotechnology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
  6. These authors contributed equally to this work.
  7. Present address: The Department of Pathology & Laboratory Medicine, New York Presbyterian Hospital, Cornell Campus, 525 East 68th Street, F511, New York, New York 10021, USA.

Correspondence to: James R. Downing1 Correspondence and requests for materials should be addressed to J.R.D. (Email: james.downing@stjude.org).

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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 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.

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