Insertional mutagenesis in gene therapy and stem cell biology
Insertional mutagenesis in gene therapy and stem cell biology
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DOI：
10.1097/moh.0b013e3281900f01
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发表时间：
2007-07-01
影响因子：
3.2
通讯作者：
Baum, Christopher
中科院分区：
文献类型：
--
作者：
Baum, Christopher
综述目的最近的临床前和临床研究表明，转基因半随机插入造血细胞的染色体DNA可能会引起克隆竞争，甚至可能引发白血病或肉瘤。因此，基因载体引起的插入突变给开发先进造血细胞疗法的人带来了很大的不确定性。这篇综述总结了潜在机制的新颖研究；这些研究证明了改善基因载体生物安全性的可能性，并产生了对干细胞生物学的新见解。最近的发现各种逆转录病毒基因载体系统的特征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。细胞培养测定和动物模型，包括疾病特异性和易患癌症的小鼠模型，正在出现，揭示了载体特征和系统因素对诱导克隆失衡的贡献。总结显性造血克隆中载体插入位点的数据库正在发展成为识别调节克隆稳态的基因的新工具。总结通过随机基因载体插入进行插入诱变的机制研究将导致先进造血细胞治疗的改进工具。同时，将产生对调节细胞健康的基因网络的令人着迷的见解，这对血液学、肿瘤学和再生医学领域产生重要影响。
Purpose of review 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.Recent findings 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.Summary 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.