Schematic representation of NOTCH1 mutations leading to increased γ-secretase processing and activation in T-ALL. Functional domains of NOTCH1 are annotated in the structure of wild-type NOTCH1. EGF-like indicates EGF-like repeats; HD, heterodimerization domain; LNR, LNR repeats; RAM, RAM domain; ankyrin, ankyrin repeats; TAD, transactivation domain; PEST, PEST domain; S2, metalloprotease cleavage site; and S3, γ-secretase cleavage site. Sequences altered by the different NOTCH1 mutations are highlighted in red. HD class 1 mutants disrupt the HD domain structure. HD class 2 mutants displace the S2 cleavage site away from the HD-LNR complex. NOTCH1 JME mutants displace the HD-LNR repeat complex away from the cell surface.