Identification of a high incidence region for retroviral vector integration near exon 1 of the LMO2 locus.
Identification of a high incidence region for retroviral vector integration near exon 1 of the LMO2 locus.
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DOI：
10.1186/1742-4690-6-79
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发表时间：
2009-09-02
期刊：
影响因子：
3.3
通讯作者：
Takeshita T
中科院分区：
文献类型：
--
作者：
Yamada K;Tsukahara T;Yoshino K;Kojima K;Agawa H;Yamashita Y;Amano Y;Hatta M;Matsuzaki Y;Kurotori N;Wakui K;Fukushima Y;Osada R;Shiozawa T;Sakashita K;Koike K;Kumaki S;Tanaka N;Takeshita T
在X-SCID基因治疗试验中，癌基因LMO 2附近的治疗性逆转录病毒载体整合被认为是白血病的原因。然而，没有发表的研究评价了LMO 2基因座外显子1附近的载体整合频率。我们使用PCR技术在TPA-Mat T细胞系中接近LMO 2转录起始位点的上游区域中鉴定了载体整合的高发生率区域（HIR）。HIR的积分频率为每4.46 × 104个细胞一次。这种HIR也在Jurkat T细胞中发现，但在HeLa细胞中不存在。此外，使用人脐带血来源的CD 34+细胞，我们在与TPA-Mat T细胞系相似的区域中鉴定了HIR。其中一名X连锁严重联合免疫缺陷（X-SCID）患者在基因治疗后发生白血病，在该HIR中有一个载体整合位点。因此，对HIR的位置和积分频率的描述有助于我们更好地理解载体诱导的白血病发生。
Therapeutic retroviral vector integration near the oncogene LMO2 is thought to be a cause of leukemia in X-SCID gene therapy trials. However, no published studies have evaluated the frequency of vector integrations near exon 1 of the LMO2 locus. We identified a high incidence region (HIR) of vector integration using PCR techniques in the upstream region close to the LMO2 transcription start site in the TPA-Mat T cell line. The integration frequency of the HIR was one per 4.46 × 104 cells. This HIR was also found in Jurkat T cells but was absent from HeLa cells. Furthermore, using human cord blood-derived CD34+ cells we identified a HIR in a similar region as the TPA-Mat T cell line. One of the X-linked severe combined immunodeficiency (X-SCID) patients that developed leukemia after gene therapy had a vector integration site in this HIR. Therefore, the descriptions of the location and the integration frequency of the HIR presented here may help us to better understand vector-induced leukemogenesis.
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