Retroviral vector insertion sites associated with dominant hematopoietic clones mark "stemness" pathways
Retroviral vector insertion sites associated with dominant hematopoietic clones mark "stemness" pathways
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DOI：
10.1182/blood-2006-08-044156
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发表时间：
2007-03-01
期刊：
影响因子：
20.3
通讯作者：
Baum, Christopher
中科院分区：
文献类型：
--
作者：
Kustikova, Olga S.;Geiger, Hartmut;Baum, Christopher
来自模式生物和临床试验的证据表明，在长期再生造血细胞的基因组中随机插入逆转录病毒载体可能会增加自我更新或引发恶性转化。非恶性细胞的克隆优势是一个特别有趣的表型，因为它可能是由影响自我更新和竞争适应性的基因失调引起的。我们已经积累了280逆转录病毒载体插入位点（RVIS）从小鼠的长期研究，导致良性或恶性克隆优势。RVIS（22.5%）位于已知原癌基因内或附近（最多100 kb [DNA酶]），49.6%位于信号基因内，27.9%位于其他或未知基因内。由此产生的插入优势数据库（IDDb）显示与造血干/祖细胞的转录组和逆转录病毒标记的癌症基因数据库（RTCGD）的大量重叠。RVIS优先标记在造血干/祖细胞中具有高表达的基因，并且基因本体论揭示了与细胞周期控制、凋亡信号传导和转录调控（包括主要的“干性”途径）相关的基因的过度表达。IDDb形成了用于鉴定刺激或转化造血干/祖细胞的基因的强大资源，并且是人类基因治疗中载体生物安全性研究的重要参考。
Evidence from model organisms and clinical trials reveals that the random insertion of retrovirus-based vectors in the genome of long-term repopulating hematopoietic cells may increase self-renewal or initiate malignant transformation. Clonal dominance of nonmalignant cells is a particularly interesting phenotype as it may be caused by the dysregulation of genes that affect self-renewal and competitive fitness. We have accumulated 280 retrovirus vector insertion sites (RVISs) from murine long-term studies resulting in benign or malignant clonal dominance. RVISs (22.5%) are located in or near (up to 100 kb [kilobase]) to known proto-oncogenes, 49.6% in signaling genes, and 27.9% in other or unknown genes. The resulting insertional dominance database (IDDb) shows substantial overlaps with the transcriptome of hematopoietic stem/progenitor cells and the retrovirus-tagged cancer gene database (RTCGD). RVISs preferentially marked genes with high expression in hematopoietic stem/progenitor cells, and Gene Ontology revealed an overrepresentation of genes associated with cell-cycle control, apoptosis signaling, and transcriptional regulation, including major "sternness" pathways. The IDDb forms a powerful resource for the identification of genes that stimulate or transform hematopoietic stem/progenitor cells and is an important reference for vector biosafety studies in human gene therapy.