The NOTCH1 oncogenic program can be therapeutically targeted by small-molecule γ-secretase inhibitors (GSIs), which effectively block NOTCH1 activation via the inhibition of a critical intramembrane proteolytic cleavage that is required for NOTCH1 signaling, making NOTCH1 signaling an important therapeutic target in T-ALL. Here, NOTCH1 is linked to acute lymphoblastic leukemia.