Notch1 mutations found in mouse T-ALL tumors fall into three main categories: (1) PEST-domain mutations, which increase the stability of N1-ICD, (2) 5′ deletions of the Notch1 locus, which result in constitutive expression of N1-ICD, and (3) Notch1 HD domain mutations, which increase Notch1 susceptibility to ligand-independent, proteolytic activation (Malecki et al., 2006), and which were detected with increased frequencies in murine T-ALL cases derived from Notch1DECRREE thymus. Here, NOTCH1 is linked to acute lymphoblastic leukemia.