Mutations that stabilize the untethered intracellular domain increase its activity and also promote T-ALL; such mutations delete the PEST domain of Notch1, or delete or inactivate Fbw7, the substrate-recognition subunit of a multiprotein ubiquitin ligase that targets Notch1 for degradation by a phosphodegron sequence located in the PEST domain (Ferrando 2009; Chiang et al. 2016). Here, FBXW7 is linked to acute lymphoblastic leukemia.