Hacein-Bey-Abina Salima, Garrigue Alexandrine, Wang Gary P, Soulier Jean, Lim Annick, Morillon Estelle, Clappier Emmanuelle, Caccavelli Laure, Delabesse Eric, Beldjord Kheira, Asnafi Vahid, MacIntyre Elizabeth, Dal Cortivo Liliane, Radford Isabelle, Brousse Nicole, Sigaux François, Moshous Despina, Hauer Julia, Borkhardt Arndt, Belohradsky Bernd H, Wintergerst Uwe, Velez Maria C, Leiva Lily, Sorensen Ricardo, Wulffraat Nicolas, Blanche Stéphane, Bushman Frederic D, Fischer Alain, Cavazzana-Calvo Marina
Department of Biotherapy, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Université René Descartes, Paris, France.
J Clin Invest. 2008 Sep;118(9):3132-42. doi: 10.1172/JCI35700.
Previously, several individuals with X-linked SCID (SCID-X1) were treated by gene therapy to restore the missing IL-2 receptor gamma (IL2RG) gene to CD34+ BM precursor cells using gammaretroviral vectors. While 9 of 10 patients were successfully treated, 4 of the 9 developed T cell leukemia 31-68 months after gene therapy. In 2 of these cases, blast cells contained activating vector insertions near the LIM domain-only 2 (LMO2) proto-oncogene. Here, we report data on the 2 most recent adverse events, which occurred in patients 7 and 10. In patient 10, blast cells contained an integrated vector near LMO2 and a second integrated vector near the proto-oncogene BMI1. In patient 7, blast cells contained an integrated vector near a third proto-oncogene,CCND2. Additional genetic abnormalities in the patients' blast cells included chromosomal translocations, gain-of-function mutations activating NOTCH1, and copy number changes, including deletion of tumor suppressor gene CDKN2A, 6q interstitial losses, and SIL-TAL1 rearrangement. These findings functionally specify a genetic network that controls growth in T cell progenitors. Chemotherapy led to sustained remission in 3 of the 4 cases of T cell leukemia, but failed in the fourth. Successful chemotherapy was associated with restoration of polyclonal transduced T cell populations. As a result, the treated patients continued to benefit from therapeutic gene transfer.
此前，数名X连锁重症联合免疫缺陷病（SCID-X1）患者接受了基因治疗，使用γ逆转录病毒载体将缺失的白细胞介素2受体γ（IL2RG）基因恢复到CD34+骨髓前体细胞中。虽然10名患者中有9名得到成功治疗，但其中9名患者中有4名在基因治疗后31 - 68个月发生了T细胞白血病。在其中2例病例中，原始细胞在仅含LIM结构域2（LMO2）原癌基因附近含有激活的载体插入。在此，我们报告最近发生在患者7和患者10身上的2起不良事件的数据。在患者10中，原始细胞在LMO2附近含有一个整合载体，在原癌基因BMI1附近含有第二个整合载体。在患者7中，原始细胞在第三个原癌基因CCND2附近含有一个整合载体。患者原始细胞中的其他遗传异常包括染色体易位、激活NOTCH1的功能获得性突变以及拷贝数变化，包括肿瘤抑制基因CDKN2A的缺失、6号染色体间质缺失和SIL-TAL1重排。这些发现从功能上明确了一个控制T细胞祖细胞生长的遗传网络。化疗使4例T细胞白血病中的3例实现了持续缓解，但第4例失败。成功的化疗与多克隆转导T细胞群体的恢复相关。因此，接受治疗的患者继续从治疗性基因转移中受益。
