PDF(Pubmed)
Abstract：
Hematopoietic stem cell gene therapy (GT) using a γ-retroviral vector (γ-RV) is an effective treatment for Severe Combined Immunodeficiency due to Adenosine Deaminase deficiency. Here, we describe a case of GT-related T-cell acute lymphoblastic leukemia (T-ALL) that developed 4.7 years after treatment. The patient underwent chemotherapy and haploidentical transplantation and is currently in remission. Blast cells contain a single vector insertion activating the LIM-only protein 2 (LMO2) proto-oncogene, confirmed by physical interaction, and low Adenosine Deaminase (ADA) activity resulting from methylation of viral promoter. The insertion is detected years before T-ALL in multiple lineages, suggesting that further hits occurred in a thymic progenitor. Blast cells contain known and novel somatic mutations as well as germline mutations which may have contributed to transformation. Before T-ALL onset, the insertion profile is similar to those of other ADA-deficient patients. The limited incidence of vector-related adverse events in ADA-deficiency compared to other γ-RV GT trials could be explained by differences in transgenes, background disease and patient\'s specific factors.
摘要：
使用γ-逆转录病毒载体（γ-RV）的造血干细胞基因治疗（GT）是由于腺苷脱氨酶缺乏引起的严重联合免疫缺陷的有效治疗方法。这里,我们描述了一例GT相关的T细胞急性淋巴细胞白血病(T-ALL),在治疗4.7年后发生.患者接受了化疗和单倍体移植，目前正在缓解。Blast细胞包含单个载体插入，激活仅LIM蛋白2（LMO2）原癌基因，通过物理相互作用证实，和由病毒启动子甲基化导致的低腺苷脱氨酶(ADA)活性。在多个谱系中的T-ALL之前几年检测到插入，表明进一步的攻击发生在胸腺祖细胞中。Blast细胞含有已知的和新的体细胞突变以及可能有助于转化的种系突变。在T-ALL发作之前，插入谱与其他ADA缺陷患者相似.与其他γ-RVGT试验相比，ADA缺乏中载体相关不良事件的发生率有限，这可以通过转基因的差异来解释。背景疾病和患者的具体因素。
