Notch signaling is initiated by interaction of N^EC with ligand on a neighboring cell. This results in cleavage of N^TM by ADAM protease followed quickly by γ-secretase cleavage, allowing the release and translocation of intracellular Notch to the nucleus. Rosati et al suggest that, in B-CLL cells, increased levels of the ligands Jagged1 and Jagged2 lead to increased Notch signaling, resulting in enhanced survival of these cells.