Here, we show that in CLL cells, PI3Kδ/AKT signaling contributes to sustaining IL-4-induced increase in Notch1-IC levels, whereas PKCδ signaling is involved in upregulating Notch2-TM and Notch2-IC levels, although the mechanisms whereby these pathways induce Notch deregulation remain undefined. Here, NOTCH2 is linked to B-cell chronic lymphocytic leukemia.