文章：

使用三种不同的全基因组筛选方法研究TEL-AML1 （ETV6-RUNX1）在前体B细胞中的表达及其对白血病的影响

The impact of TEL-AML1 (ETV6-RUNX1) expression in precursor B cells and implications for leukaemia using three different genome-wide screening methods

原文发布日期：2013-10-11

DOI: 10.1038/bcj.2013.48

类型: Original Article

开放获取: 是

英文摘要：

The reciprocal translocation t(12;21)(p13;q22), the most common structural genomic alteration in B-cell precursor acute lymphoblastic leukaemia in children, results in a chimeric transcription factor TEL-AML1 (ETV6-RUNX1). We identified directly and indirectly regulated target genes utilizing an inducible TEL-AML1 system derived from the murine pro B-cell line BA/F3 and a monoclonal antibody directed against TEL-AML1. By integration of promoter binding identified with chromatin immunoprecipitation (ChIP)-on-chip, gene expression and protein output through microarray technology and stable labelling of amino acids in cell culture, we identified 217 directly and 118 indirectly regulated targets of the TEL-AML1 fusion protein. Directly, but not indirectly, regulated promoters were enriched in AML1-binding sites. The majority of promoter regions were specific for the fusion protein and not bound by native AML1 or TEL. Comparison with gene expression profiles from TEL-AML1-positive patients identified 56 concordantly misregulated genes with negative effects on proliferation and cellular transport mechanisms and positive effects on cellular migration, and stress responses including immunological responses. In summary, this work for the first time gives a comprehensive insight into how TEL-AML1 expression may directly and indirectly contribute to alter cells to become prone for leukemic transformation.

摘要翻译： 

儿童B细胞前体型急性淋巴细胞白血病（ALL）是一种治愈率较高的疾病，然而部分患者的治疗耐药性以及现有疗法的长期毒性作用，使得开发更具靶向性的治疗方法成为必要。我们研究了JQ1（一种针对转录调节因子溴结构域和超末端结构域（BET）蛋白家族的高选择性抑制剂）在儿童ALL中的细胞毒性作用。研究发现，JQ1对一组原发性ALL细胞株表现出强效的体外细胞毒性反应，这种反应不依赖于其预后特征，而是与高MYC表达相关，并伴随多种促生存通路的转录下调。与早期研究一致，JQ1可诱导细胞周期停滞。本研究进一步表明，BET抑制还能降低c-Myc蛋白稳定性，并抑制ALL细胞中DNA复制叉的进展。与c-Myc耗竭和促生存通路下调的结果一致，JQ1使原发性ALL样本对经典ALL治疗药物地塞米松的敏感性增强。最后，我们证实JQ1在ALL异种移植模型中能单药或联合地塞米松共同抑制白血病生长。我们得出结论：靶向BET蛋白应被视为治疗儿童ALL的新策略，特别是对标准治疗反应不佳的病例。

原文链接：

The impact of TEL-AML1 (ETV6-RUNX1) expression in precursor B cells and implications for leukaemia using three different genome-wide screening methods