At variance with T-ALL where mutations in NOTCH1 HD facilitate ligand-independent activation (67), triggering of NOTCH1 signaling in CLL strictly relies on the interaction with the ligand(s), even in the presence of PEST mutations, as these lesions result in the stabilization of ligand-triggered cleaved NOTCH1 rather than in autonomous signaling activation (57). The gene discussed is NOTCH1; the disease is acute lymphoblastic leukemia.