Increased activity of NOTCH1 pathway protects leukemic cells from apoptosis through multiple mechanisms, among which the crosstalk with NF-κB signaling represents a key feature in CLL biology, as it directly regulates expression of anti-apoptotic genes (e.g., c-IAP2 and XIAP) and surface molecules (e.g., CD49d) that facilitate interactions with microenvironment, feeding a pro-leukemic loop (58) (Figure 4). This evidence concerns the gene ITGA4 and B-cell chronic lymphocytic leukemia.