Zielzellen insertioneller Transformation in der Hämatopoese

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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.