LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1
LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1
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DOI：
10.1126/science.1088547
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发表时间：
2003-10-17
期刊：
影响因子：
56.9
通讯作者：
Cavazzana-Calvo, M
中科院分区：
文献类型：
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作者：
Hacein-Bey-Abina, S;Von Kalle, C;Cavazzana-Calvo, M
我们之前已经证明，通过逆转录病毒介导的gammac基因转移到自体CD 34骨髓细胞中，10例患者中有9例X连锁严重联合免疫缺陷[SCID-X1，也称为γ链（gammac）缺陷]得到纠正。然而，基因治疗后近3年，在两名最年轻的患者中发生了成熟T细胞（具有γ δ +或α + T细胞受体）的不受控制的指数克隆增殖。两名患者的克隆显示逆转录病毒载体整合在LMO 2原癌基因启动子附近，导致LMO 2的异常转录和表达。因此，逆转录病毒载体的插入可以触发失调癌前细胞增殖与意想不到的频率，最有可能是由逆转录病毒增强子活性的LMO 2基因启动子。
We have previously shown correction of X-linked severe combined immunodeficiency [SCID-X1, also known as gamma chain (gammac) deficiency] in 9 out of 10 patients by retrovirus-mediated gammac gene transfer into autologous CD34 bone marrow cells. However, almost 3 years after gene therapy, uncontrolled exponential clonal proliferation of mature T cells (with gammadelta+ or alphabeta+ T cell receptors) has occurred in the two youngest patients. Both patients' clones showed retrovirus vector integration in proximity to the LMO2 proto-oncogene promoter, leading to aberrant transcription and expression of LMO2. Thus, retrovirus vector insertion can trigger deregulated premalignant cell proliferation with unexpected frequency, most likely driven by retrovirus enhancer activity on the LMO2 gene promoter.