NOTCH1 and leukemia: NOTCH1 mutations in CLL mainly clusters within a hotspot in exon 34, and are commonly represented by a single 2-bp deletion (c.7544_7545delCT) that accounts for ~80–95% of all NOTCH1 mutations in this leukemia (Figure 1).10–12,14,16,51–53 The predicted functional consequence of NOTCH1 mutations in CLL is the disruption of the C-terminal PEST domain resulting in activated NOTCH1 protein, impaired degradation and accumulation, and sustaining deregulated signaling.11 Consistent with this notion, a number of cellular pathways are specifically altered in CLL harboring NOTCH1 mutations.11,52