Boulianne Bryant, Robinson Mark E, May Philippa C, Castellano Leandro, Blighe Kevin, Thomas Jennifer, Reid Alistair, Müschen Markus, Apperley Jane F, Stebbing Justin, Feldhahn Niklas
Centre for Haematology, Department of Medicine, Imperial College London, W12 0NN London, UK.
Centre for Haematology, Department of Medicine, Imperial College London, W12 0NN London, UK; Division of Cancer, Department of Surgery and Cancer, Imperial College London, W12 0NN London, UK.
Cell Rep. 2017 Feb 14;18(7):1687-1698. doi: 10.1016/j.celrep.2017.01.057.
In human leukemia, lineage-specific genes represent predominant targets of deletion, with lymphoid-specific genes frequently affected in lymphoid leukemia and myeloid-specific genes in myeloid leukemia. To investigate the basis of lineage-specific alterations, we analyzed global DNA damage in primary B cell precursors expressing leukemia-inducing oncogenes by ChIP-seq. We identified more than 1,000 sensitive regions, of which B lineage-specific genes constitute the most prominent targets. Identified hotspots at B lineage genes relate to DNA-DSBs, affect genes that harbor genomic lesions in human leukemia, and associate with ectopic deletion in successfully transformed cells. Furthermore, we show that most identified regions overlap with gene bodies of highly expressed genes and that induction of a myeloid lineage phenotype in transformed B cell precursors promotes de novo DNA damage at myeloid loci. Hence, we demonstrate that lineage-specific transcription predisposes lineage-specific genes in transformed B cell precursors to DNA damage, which is likely to promote the frequent alteration of lineage-specific genes in human leukemia.
在人类白血病中，谱系特异性基因是缺失的主要靶点，淋巴样特异性基因在淋巴样白血病中经常受到影响，而髓样特异性基因在髓样白血病中常受影响。为了研究谱系特异性改变的基础，我们通过染色质免疫沉淀测序（ChIP-seq）分析了表达白血病诱导癌基因的原代B细胞前体中的全基因组DNA损伤。我们鉴定出1000多个敏感区域，其中B谱系特异性基因是最主要的靶点。在B谱系基因处鉴定出的热点与DNA双链断裂（DNA-DSBs）有关，影响人类白血病中含有基因组损伤的基因，并与成功转化细胞中的异位缺失相关。此外，我们表明，大多数鉴定出的区域与高表达基因的基因体重叠，并且在转化的B细胞前体中诱导髓样谱系表型会促进髓样基因座处的新生DNA损伤。因此，我们证明谱系特异性转录使转化的B细胞前体中的谱系特异性基因易发生DNA损伤，这可能促进人类白血病中谱系特异性基因的频繁改变。
