Can polyclonality prevent oncogenesis?

Datum

31.03.2011

Zeit

14:30 - 15:30

Sprecher

Sebastian Gerdes

Zugehörigkeit

Institute for Medical Informatics and Biometry, TU Dresden

Serie

IMB - Seminar

Sprache

en

Hauptthema

Medizin

Andere Themen

Medizin, Informatik

Host

Ingo Roeder

Beschreibung

T cell receptor (TCR) polyclonal mature T cells are surprisingly resistant to oncogenic transformation through retroviral induction of T cell oncogenes. It has been shown that leukemia/lymphoma did not occur upon transplantation of polyclonal T cells into RAG1-1-deficient recipients, although the T-cells were transduced with high copy numbers of gammaretroviral vectors encoding potent T cell oncogenes [1]. Interestingly, further studies demonstrated that the transplantation of T cells from TCR monoclonal OT1 mice that were transduced with the same protocol resulted in leukemia/lymphoma. The underlying mechanisms that prevent oncogenesis in the polyclonal situation and endorse the outbreak of leukemia in the monoclonal situation are currently unclear. Using a mathematical modelling approach, we challenge the arising hypothesis that in the polyclonal situation, the emergence of a leukemic clone is inhibited due to clonal competition for survival stimuli with healthy competitor clones. As a starting point, we developed a simple model of T cell homeostasis emphasizing the analogy of T cell homeostasis to species coexisting in ecological niches. The key assumption of the model is that T cell survival is critically dependent on the interaction of the clone-specific TCR with self-peptide-MHC-complexes (corresponding to environmental niches). Based on our modelling results, we speculate about the cellular properties of the leukemic clone. Within our model framework, we are able to explain the observed phenomena under the following two assumptions concerning the cellular properties of the leukemic clone: (i) The leukemic clone is less competent than other T cell clones in acquiring survival stimuli from niches. (ii) Proliferation of the leukemic clone is less dependent on niche interaction. From our results, we conclude that clonal competition is a possible mechanism to counterbalance clonal dominance. The modelling results are used to foster the design of further biological experiments. A future goal is to determine the minimum clonal complexity that is needed in order to control the leukemic clone under the given circumstances. References: [1] Newrzela S, Cornils K et al. Resistance of mature T cells to oncogene trans- formation. Blood. 2008;112(6):2278–2286.

Letztmalig verändert: 25.03.2011, 18:07:07