Baum Christopher
Department of Experimental Hematology, Hannover Medical School, Hannover, Germany.
Curr Opin Hematol. 2007 Jul;14(4):337-42. doi: 10.1097/MOH.0b013e3281900f01.
Recent preclinical and clinical studies revealed that the semirandom insertion of transgenes into chromosomal DNA of hematopoietic cells may induce clonal competition, which potentially may even trigger leukemia or sarcoma. Insertional mutagenesis caused by gene vectors has thus led to major uncertainty among those developing advanced hematopoietic cell therapies. This review summarizes novel studies of underlying mechanisms; these studies have demonstrated the possibility of improved gene vector biosafety and generated new insights into stem cell biology.
The characteristic insertion pattern of various retroviral gene vector systems may be explained by properties of the viral integrase and associated cellular cofactors. Cell culture assays and animal models, including disease-specific and cancer-prone mouse models, are emerging that reveal the contributions of vector features and systemic factors to induction of clonal imbalance. Databases summarizing vector insertion sites in dominant hematopoietic clones are evolving as new tools to identify genes that regulate clonal homeostasis.
Mechanistic studies of insertional mutagenesis by random gene vector insertion will lead to improved tools for advanced hematopoietic cell therapy. Simultaneously, fascinating insights into gene networks that regulate cell fitness will be generated, with important consequences for the fields of hematology, oncology and regenerative medicine.
近期的临床前和临床研究表明，转基因在造血细胞染色体DNA中的半随机插入可能引发克隆竞争，甚至有可能引发白血病或肉瘤。因此，基因载体引起的插入诱变在那些开发先进造血细胞疗法的人群中引发了重大的不确定性。本综述总结了关于潜在机制的新研究；这些研究证明了改善基因载体生物安全性的可能性，并对干细胞生物学产生了新的见解。
各种逆转录病毒基因载体系统的特征性插入模式可以通过病毒整合酶和相关细胞辅助因子的特性来解释。细胞培养试验和动物模型，包括疾病特异性和易患癌症的小鼠模型，正在不断涌现，揭示了载体特征和全身因素对克隆失衡诱导的作用。总结优势造血克隆中载体插入位点的数据库正在不断发展，成为识别调节克隆稳态基因的新工具。
对随机基因载体插入引起的插入诱变进行机制研究，将为先进的造血细胞治疗带来更好的工具。同时，将对调节细胞适应性的基因网络产生迷人的见解，这将对血液学、肿瘤学和再生医学领域产生重要影响。
