The most common NOTCH1 mutations in T-ALL derange the structure of the NRR (Malecki et al. 2006), leading to ligand-independent ICN generation and overexpression of key target genes such as MYC, mainly via interaction of ICN/RBPJ complexes with long-range enhancers (Herranz et al. 2014; Yashiro-Ohtani et al. 2014). This evidence concerns the gene MYC and acute lymphoblastic leukemia.