In this project we aim to improve the knowledge on how aberrant splicing regulation of the proteostasis network impact T-cell acute lymphoblastic leukemia (T-ALL) initiation and pathogenesis. We believe improved understanding of leukemia biology may provide novel therapeutic strategies for pediatric and adult patients that may respond insufficiently to standard-of-care chemotherapy regiments or do so experiencing the severe toxicities associated with high-dose combination therapy, including developing secondary tumors later in life. Although previous clinical studies of the proteasome inhibitor Bortezomib did not demonstrate superior survival in T-ALL patients, we aim to study whether targeting the therapeutic vulnerability of splicing regulation of the proteasome in T-ALL through combination therapy with spliceosome or deubiquitinase inhibitors may improve response. Furthermore, improving our understanding of the interplay between these mechanisms in T-ALL may allow to select patients based on characteristics including expression profile or subtype, to determine patients that might benefit more from proteasome inhibition, helping the move towards patient stratification and personalized medicine.