NOTCH1 and T-cell acute lymphoblastic leukemia: Notably, gain-of-function mutations in Notch that are found in more than 50% of cases of childhood cancer T-cell acute lymphoblastic leukemia (T-ALL) result from point mutations in the Notch1 NRR, which cause the destabilization of the NRR and result in constitutive access to the Notch S2 site and Notch activation [24,26,27].