Canonical NOTCH signaling is induced by ligand binding, the intracellular domain of NOTCH (NIC) is released by a series of proteolytic events involving γ-secretase followed by translocation to the nucleus, where it acts as context and cell type specific transcription factor on CSL (for CBF1, Suppressor of Hairless, and LAG-1)-responsive genes like FCER2 (CD23) in CLL cells [7,18,20,21,22]. The gene discussed is FCER2; the disease is B-cell chronic lymphocytic leukemia.