Interestingly, this suggested PEST-independent interaction mechanism might explain the observation of USP28 inhibition reducing NICD levels in CLL patients with PEST-deleting NOTCH1 mutations, but raises questions about other domains of the NOTCH1 protein that might facilitate the USP28/NICD interaction and NOTCH1 stabilization in CLL. Here, USP28 is linked to B-cell chronic lymphocytic leukemia.