During the last years a number of improvements with regard to gene transfer vectors and transduction protocols have been achieved. On this basis, the possibility to efficiently introduce genetic modifications in cells has improved considerably. As shown in clinical trials, these methods can successfully be applied in gene therapeutic approaches. Despite these successes, it is still unresolved why some clones with vector insertions in particular gene loci become dominant while others do not. The mechanisms driving clonal dominance and potentially leukaemic transformation after gene vector insertions are widely unknown. There is also evidence that mature T cells are less susceptible to leukaemic transformation than haematopoietic stem cells, another potentially important but still unexplained observation.
It is our objective to contribute to the process of answering these questions by the application of systems biological methods. In the project we will refine, extend, and validate a mathematical model that is able to predict clonal dynamics in vivo. The project directly builds on the results obtained in the first funding period of this Research Priority Program. In particular, we will incorporate qualitatively new experimental and clinical data, such as large-scale measurements of individual clone dynamics on the basis of the next generation (pyro-)sequencing technology, the quantification of individual clones by insertion site specific quantitative RT-PCR methods, and by the use of promoter-deprived vector systems as neutral markers for individual clones, into the modelling process. Furthermore, we are going to extend the mathematical model to comprise also clonal dynamics of mature T cells.

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