Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells

Abstract

Notch signaling is involved in tumorigen- esis, but its role in B-chronic lympho- cytic leukemia (B-CLL) pathogenesis is not completely defined. This study exam- ined the expression and activation of Notch receptors in B-CLL cells and the role of Notch signaling in sustaining the survival of these cells. Our results show that B-CLL cells but not normal B cells constitutively express Notch1 and Notch2 proteins as well as their ligands Jagged1 and Jagged2. Notch signaling is constitu- tively activated in B-CLL cells, and its activation is further increased in B-CLL cells, which resist spontaneous apopto- sis after 24-hour ex vivo culture. Notch stimulation by a soluble Jaggedl ligand increases B-CLL cell survival and is ac- companied by increased nuclear factor- kappa B (NF-KB) activity and cellular inhibitor of apoptosis protein 2 (C-IAP2) and X-linked inhibitor of apoptosis pro- tein (XIAP) expression. In contrast, Notch- signaling inhibition by the ?-secretase inhibitor I (GSI; z-Leu-Leu-Nle-CHO) and the specific Notch2 down-regulation by small-interfering RNA accelerate sponta- neous B-CLL cell apoptosis. Apoptotic activity of GSI is accompanied by reduc- tion of NF-KB activity and C-IAP2 and XIAP expression. Overall, our findings show that Notch signaling plays a critical role in B-CLL cell survival and apoptosis resistance and suggest that it could be a novel potential therapeutic target. © 2009 by The American Society of Hematology.