Objetivo "Clonal evolution represents a central feature of tumor progression and relapse. Chronic lymphocytic leukemia (CLL) is a valuable model to study this process due to a high prevalence, initially slow progression and the easy availability of samples. Recent large-scale sequencing studies have identified putative driver genetic events of CLL, uncovered the vast inter-personal and intratumoral genetic heterogeneity in CLL and have linked the presence of aggressive subclonal mutations with clonal evolution and poorer outcome. The patterns of different aberrations within the same sample suggest a temporal hierarchy in acquisition of genetic events, and a stepwise transformation of disease from diagnosis to later more aggressive stages. To directly test these ideas, I will systematically examine the clonal dynamics of a cohort of 17 CLL patients that were recurrently sampled over years from diagnosis until the time of first treatment. Through this longitudinal study, I will seek to identify the early events in this initially indolent malignancy leading to disease progression and how the order of genomic aberrations dictates tumor fate and biology (Aim 1). To directly test the functional impact of these early genetic events on B cell biology, we will utilize novel TALEN genome-engineering technology to generate cell lines harboring key mutation events (Aim 2). The generation of these isogenic cell lines will enable me to determine the relative fitness of putative CLL drivers in vitro and to study the effect of established and novel cytotoxic and targeted drugs on the dynamics amongst CLL subpopulations (Aim 3).Answering these questions will facilitate translation of novel genetic insights towards the development of individualized diagnostic and therapeutic management of CLL." Ámbito científico natural sciencesbiological sciencescell biologynatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesclinical medicineoncologyleukemia Programa(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Tema(s) FP7-PEOPLE-2013-IOF - Marie Curie Action: "International Outgoing Fellowships for Career Development" Convocatoria de propuestas FP7-PEOPLE-2013-IOF Consulte otros proyectos de esta convocatoria Régimen de financiación MC-IOF - International Outgoing Fellowships (IOF) Coordinador MEDIZINISCHE UNIVERSITAET WIEN Aportación de la UE € 260 874,60 Dirección SPITALGASSE 23 1090 Wien Austria Ver en el mapa Región Ostösterreich Wien Wien Tipo de actividad Higher or Secondary Education Establishments Contacto administrativo Ulrich Jaeger (Prof.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Coste total Sin datos