Treatment with γ-secretase inhibitors induces apoptosis of CLL cells by inhibiting the enzymatic S3 cleavage necessary for NOTCH1 activation.47,54,55 However, the limitations due to toxicity of γ-secretase inhibitors in the clinical setting suggest that alternative strategies may be needed for the therapeutic targeting of NOTCH1. Here, NOTCH1 is linked to B-cell chronic lymphocytic leukemia.