Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack M P, Wulffraat N, Leboulch P, Lim A, Osborne C S, Pawliuk R, Morillon E, Sorensen R, Forster A, Fraser P, Cohen J I, de Saint Basile G, Alexander I, Wintergerst U, Frebourg T, Aurias A, Stoppa-Lyonnet D, Romana S, Radford-Weiss I, Gross F, Valensi F, Delabesse E, Macintyre E, Sigaux F, Soulier J, Leiva L E, Wissler M, Prinz C, Rabbitts T H, Le Deist F, Fischer A, Cavazzana-Calvo M
INSERM Unit 429, Cedex 15, France.
Science. 2003 Oct 17;302(5644):415-9. doi: 10.1126/science.1088547.
We have previously shown correction of X-linked severe combined immunodeficiency [SCID-X1, also known as gamma chain (gamma(c)) deficiency] in 9 out of 10 patients by retrovirus-mediated gamma(c) 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.
我们之前已经证明，通过逆转录病毒介导的γ(c)基因转移至自体CD34骨髓细胞，10名X连锁严重联合免疫缺陷症（SCID-X1，也称为γ链缺乏症）患者中有9名得到了纠正。然而，在基因治疗近3年后，两名最年轻的患者出现了成熟T细胞（具有γδ+或αβ+ T细胞受体）不受控制的指数级克隆增殖。两名患者的克隆均显示逆转录病毒载体整合在LMO2原癌基因启动子附近，导致LMO2异常转录和表达。因此，逆转录病毒载体插入可引发频率意外的失控癌前细胞增殖，最有可能是由LMO2基因启动子上的逆转录病毒增强子活性驱动的。
