Pediatric T-cell lymphoblastic lymphoma (T-LBL) is an aggressive hematological cancer with distinct molecular and clinical characteristics compared to its leukemic counterpart, T-cell acute lymphoblastic leukemia (T-ALL). Despite the identification of the prognostic relevance of NOTCH1 mutations, the current molecular understanding of the disease remains insufficient. Recent research has revealed that a subgroup of patients (~20%) with an extremely poor prognosis is characterized by the presence of NOTCH1 fusions. In this project, I aim to systematically characterize the molecular effects of NOTCH1 fusions in T-LBL. Using a unique multi-omics workflow, conducted in collaboration with the laboratory of the co-supervisors (Prof. Steven Goossens, Dr. Maarten Dhaenens), I will generate and integrate genomic, epigenomic, transcriptomic, proteomic, and metabolomic data for a selected cohort of NOTCH1 fusion-positive and fusion-negative patients. This multi-omics approach, combined with available clinical data, will enable me to thoroughly investigate the underlying biological mechanisms and clinical outcomes of this subgroup. By transplanting murine pro-T cells transduced to overexpress these fusions, I will determine tumor latency and establish murine tumor cell cultures. Additionally, I will generate primary patient-derived xenografts, which will provide sufficient biological material for drug response profiling (DRP) using an in-house platform (>150 drugs). These results will lay the foundation for personalized targeted therapies for this high-risk subgroup.