B1: Genomic instability, disease evolution and rational treatment development in CLL mouse models
In the era of novel agents for CLL therapy, several established prognostic factors lose their importance, with different CLL subsets showing remarkable responses. Recently, genomic complexity was suggested to be a prognostic factor for response to ibrutinib1, a BTK inhibitor with tremendous clinical success, indicating that genomic alterations may still be relevant in the context of novel treatments. Telomere dysfunction is a known contributor to genomic instability, and its role in genomic complexity of CLL is unknown. In the pro-posed project, the association of telomere length with disease characteristics and response to novel thera-py will be assessed in clinical trial cohorts. In parallel, genomic instability and high-risk CLL will be modelled in vivo by serially transferring tumors from TCL1+ mTerc-/- mice and by crossing the TCL1+ mTerc-/- mouse with the p53 knockout mouse, respectively. Recurrent genomic alterations arising in the mouse models will be screened and their impact on novel drugs will be analyzed. Furthermore, murine tumors will be used in vivo for sequential and combinatorial testing of novel drugs for the best efficacy, one of the central questions in the context of clinical application of the novel agents in CLL.
For a current list of project-related publications, please go to this page