Lentiviral vector common integration sites in preclinical models and a clinical trial reflect a benign integration bias and not oncogenic selection
Lentiviral vector common integration sites in preclinical models and a clinical trial reflect a benign integration bias and not oncogenic selection
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DOI：
10.1182/blood-2010-09-306761
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发表时间：
2011-05-19
期刊：
影响因子：
20.3
通讯作者：
Montini, Eugenio
中科院分区：
文献类型：
--
作者：
Biffi, Alessandra;Bartholomae, Cynthia C.;Montini, Eugenio
最近的一项肾上腺脑白质营养不良（ALD）的临床试验显示了慢病毒载体（LV）基因转移在造血干祖细胞中的有效性和安全性。然而，在患者细胞中发现了几个常见的插入位点（CIS），表明LV整合具有选择性优势。我们对移植到免疫缺陷小鼠中的人造血干祖细胞进行了高通量LV整合位点分析，发现了与ALD患者相同的CIS。引人注目的是，在我们的实验模型和ALD患者中，大多数CIS聚集在LV整合密度高的兆碱基宽的染色体区域。相反，在来自基于γ逆转录病毒载体的临床试验和小鼠癌基因标记筛选的肿瘤细胞中发现的CIS处的癌症触发整合总是靶向单个基因，并且包含在狭窄的基因组间隔中。这些发现意味着LV CIS是由对特定基因组区域的整合偏好而不是致癌选择产生的。（血。2011;117（20）：5332-5339）
A recent clinical trial for adrenoleukodystrophy (ALD) showed the efficacy and safety of lentiviral vector (LV) gene transfer in hematopoietic stem progenitor cells. However, several common insertion sites (CIS) were found in patients' cells, suggesting that LV integrations conferred a selective advantage. We performed high-throughput LV integration site analysis on human hematopoietic stem progenitor cells engrafted in immunodeficient mice and found the same CISs reported in patients with ALD. Strikingly, most CISs in our experimental model and in patients with ALD cluster in megabase-wide chromosomal regions of high LV integration density. Conversely, cancer-triggering integrations at CISs found in tumor cells from gamma retroviral vector-based clinical trials and oncogene-tagging screenings in mice always target a single gene and are contained in narrow genomic intervals. These findings imply that LV CISs are produced by an integration bias toward specific genomic regions rather than by oncogenic selection. (Blood. 2011;117(20):5332-5339)