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摘要 : 根据美国和英国研究人员的最新研究成果显示,基因重排是造成儿童白血病的主要成因之一。而基因重排被认为是人体免疫系统抗体多样性的根本原因之一。相关文章发表于2014年1月12日的《Nature genetics》杂志上。
Nature Genetics:英美发现基因重排是造成儿童白血病主因之一


根据美国和英国研究人员的最新研究成果显示,基因重排是造成儿童白血病的主要成因之一。而基因重排被认为是人体免疫系统抗体多样性的根本原因之一。相关文章发表于2014年1月12日的《Nature genetics》杂志上。





RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia

Elli Papaemmanuil, Inmaculada Rapado, Yilong Li, Nicola E Potter, David C Wedge, Jose Tubio, Ludmil B Alexandrov, Peter Van Loo, Susanna L Cooke, John Marshall, Inigo Martincorena, Jonathan Hinton, Gunes Gundem, frederik W van Delft, Serena Nik-Zainal,David R Jones, Manasa Ramakrishna, Ian Titley, Lucy Stebbings, Catherine Leroy, Andrew Menzies, John Gamble, Ben Robinson, Laura Mudie, Keiran Raine et al.

The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL) cases, is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, characterized by recombination signal sequence motifs near breakpoints, incorporation of non-templated sequence at junctions, ~30-fold enrichment at promoters and enhancers of genes actively transcribed in B cell development and an unexpectedly high ratio of recurrent to non-recurrent structural variants. Single-cell tracking shows that this mechanism is active throughout leukemic evolution, with evidence of localized clustering and reiterated deletions. Integration of data on point mutations and rearrangements identifies ATF7IP and MGA as two new tumor-suppressor genes in ALL. Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1–positive lymphoblasts, targeting the promoters, enhancers and first exons of genes that normally regulate B cell differentiation.

来源: Nature 浏览次数:69


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