Vector integration is nonrandom and clustered and influences the fate of lymphopoiesis in SCID-X1 gene therapy
Vector integration is nonrandom and clustered and influences the fate of lymphopoiesis in SCID-X1 gene therapy
复制标题
DOI：
10.1172/jci31659
复制
发表时间：
2007-08-01
影响因子：
15.9
通讯作者：
Cavazzana-Calvo, Marina
中科院分区：
文献类型：
--
作者：
Deichmann, Annette;Hacein-Bey-Abina, Salima;Cavazzana-Calvo, Marina
最近的报告挑战了逆转录病毒和逆转录病毒载体随机整合到宿主基因组中的观念。这些报告指出，在基因编码区和基因编码区附近，以及转录起始位点周围的γ -逆转录病毒载体的整合存在强烈的倾向。在这里，我们报告了从9例接受逆转录病毒基因治疗的x连锁SCID （SCID- x1）患者的细胞中分离的572个逆转录病毒整合位点（RlSs）的大规模定位结果。我们的数据显示，三分之二的插入发生在基因中或非常接近基因，其中一半以上在CD34（+）祖细胞中高度表达。引人注目的是，四分之一的集成被聚集为公共集成站点（CISs）。CISs在循环T细胞中的高度显著发生率及其位置的性质表明，插入许多基因位点对细胞植入、存活和增殖有影响。除了观察到的3例插入突变病例外，这些数据有助于阐明人类SCID-X1患者的载体插入与转导细胞的长期体内选择之间的关系。
Recent reports have challenged the notion that retroviruses and retroviral vectors integrate randomly into the host genome. These reports pointed to a strong bias toward integration in and near gene coding regions and, for gammaretroviral vectors, around transcription start sites. Here, we report the results obtained from a large-scale mapping of 572 retroviral integration sites (RlSs) isolated from cells of 9 patients with X-linked SCID (SCID-X1) treated with a retrovirus-based gene therapy protocol. Our data showed that two-thirds of insertions occurred in or very near to genes, of which more than half were highly expressed in CD34(+) progenitor cells. Strikingly, one-fourth of all integrations were clustered as common integration sites (CISs). The highly significant incidence of CISs in circulating T cells and the nature of their locations indicate that insertion in many gene loci has an influence on cell engraftment, survival, and proliferation. Beyond the observed cases of insertional mutagenesis in 3 patients, these data help to elucidate the relationship between vector insertion and long-term in vivo selection of transduced cells in human patients with SCID-X1.