Zielzellen insertioneller Transformation in der Hämatopoese

越来越多的证据表明，基因转移载体随机插入造血细胞基因组可能会对其体内差异克隆选择产生实质性影响。由逆转录病毒载体插入原癌基因或其他信号基因(附近)而引发的克隆性优势已被描述为正常和恶性造血。然而，作为体细胞转基因的副作用的插入突变的结果在多大程度上与(1)靶细胞的mtrinsinc特性，(2)影响体内克隆竞争的外部环境因素，以及(3)转基因载体的类型有关，目前尚不清楚。本提案在小鼠骨髓移植(BMT)模型中解决了这些问题，假设生物体内的克隆选择可能起源于其他短暂的祖细胞，并受到应激造血环境条件和次优载体技术的促进。我们的工作可能会为改进基因治疗临床试验的设计提供理论基础，并对细胞自我更新和转化的基本过程产生新的见解。

Increasing evidence reveals that random insertion of gene transfer vectors into the genome of hematopoietic cells may have substantial consequences for their differential clonal selection in vivo. Clonal dominance triggered by retroviral vector insertions in (the vicinity of) proto-oncogenes or other signalling genes has been described for both normal and malignant hematopoiesis. However, it is unknown to what extent the outcome of insertional mutagenesis as a side effect of somatic \ transgenesis is related to (1) mtrinsinc properties of the target cell, (2) extrinsic environmental factors influencing clonal competition in vivo, and (3) the type of transgene vectors. The present proposal addresses these questions in murine models of bone marrow transplantation (BMT), hypothesizing that clonal selection within the organism may originate from otherwise short-lived progenitor cells and is promoted by milieu conditions of stress hematopoiesis and suboptimal vector technology. Our work may provide a rationale for the improved design of clinical trials in gene therapy and generate new insights into fundamental processes of cellular self-renewal and transformation.