Do retroviral vector insertions influence the fate of terminally differentiated cells such as T lymphocytes by insertional mutagenesis?

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Gene transfer with (y-)retroviral (RV) vectors into hematopoietic stem and progenitor cells may heavily influence the fate of single cells eventually leading to clonal dominance or even malignant transformation. The observed survival advantage of those clones has been attributed to random vector insertions into proto-oncogenes or other signaling genes. However, it is not known yet whether such strong side effects of retroviral vector insertions may also be expected with terminally differentiated cells. We here aim at investigating this question using peripheral T cells, an important target of various gene therapy strategies. We will perform dose-escalated T cell transduction with both y-retro and lentiviral vectors and analyze the long-term impact of insertion sites in vitro and in vivo, in murine BMT models. Vectors with strong promotor/enhancer elements developed by our partner Baum will be used to mimic a worst case scenario . In cooperation with other applicants of this SPP1230 (Frühauf, von Laer, von Kalle) we will also analyze RV vector insertions in T cells from clinical gene therapy samples. Together this data should allow to get novel insights into the risk of malignant transformation of T lymphocytes by both y-retro- and lentiviral gene transfer. Through a network of cooperation this project will also significantly contribute to several of the common platforms of the given SPP, incl. insertional genomics, models of clonat selection, mathematical modeling and vectorology.