NOTCH3 and acute lymphoblastic leukemia: In addition to amplification, mutations in the negative regulatory region (NRR) and proline (P), glutamic acid (E), serine (S), threonine (T)-rich (PEST) domains of Notch3 gene can cause Notch3 activation (gain-of-function/activating mutations), as seen in human T-cell acute lymphoblastic leukemia (T-ALL) (Bernasconi-Elias et al., 2016).