Aneuploidy is the most common genetic abnormality in pediatric cases of B-cell acute lymphoblastic leukemia (B-ALL). However, the origin of aneuploid karyotypes and its consequences for B-ALL progression are unknown. Our group uses a broad range of cell biology, molecular biology, -omics methods, and patient-derived xenograft (PDX) mice models to study the origin and pathogenesis of aneuploidy in childhood B-ALL aiming to identify novel therapeutic targets involved in aneuploidy and CIN tolerance. In my talk I will present recent data from our group, involving the ongoing collaboration of MOLAB, as well as our most immediate and long-terms plans.