An exhaustive metabolomic research project, focusing on gamma secretase inhibitor (GSI) resistance in a T-ALL mouse model, demonstrated that in NOTCH1-driven T-ALL, the mutational background of PTEN, a negative regulator of the PI3K/Akt cascade, contributes to a metabolic rewiring as a consequence of GSI treatment. Here, AKT1 is linked to acute lymphoblastic leukemia.