T cell acute lymphoblastic leukemia (T-ALL) is an aggressive T cell malignancy that is most common in children and adolescents. Our current understanding of the molecular genetics of T-ALL indicates that leukemic transformation of thymocytes is caused by the cooperation of mutations that affect proliferation, survival, cell cycle, differentiation and self renewal. Molecular analysis has identified a large number of T-ALL specific oncogenes, but the genetic defects that are implicated in the aberrant proliferation and survival of the leukemic cells remain largely unknown. It is the aim of this project to continue the molecular characterization of T-ALL using genome wide analyses, focused RNAi screens, and drug library screens to identify oncogenes that specifically provide proliferation and survival advantages, as well as other targets for therapy in T-ALL. In addition, we will study the cooperation of these oncogenes with other oncogenic events using in vitro and in vivo mouse models, and use those models for the development and characterization of novel therapeutics. This project will generate novel insights in the molecular pathogenesis of T-ALL and aims at translating this information towards novel targeted therapies.