NOTCH1 signaling is dysregulated by loss of the deubiquitinase USP28 with del(11q), uncovering USP28 inhibition as novel therapeutic target in CLL.

ABSTRACT: Aberrant active NOTCH1 signaling is a key pathogenic factor in chronic lymphocytic leukemia (CLL), detectable in half of patients and associated with disease progression. While some cases of active NOTCH1 signaling can be explained by mutations in NOTCH1 or its regulators, like FBXW7, alternative mechanisms remain elusive. Here, we identified the deubiquitinase USP28 as regulator of NOTCH1 signaling in CLL. Notably, USP28 is located within the frequently deleted chr11q23 region and is deleted in 90% of del(11q) patients, resulting in its decreased expression. USP28 interacts with the NOTCH1 intracellular domain (NICD) independently of FBXW7 and the NICD-PEST domain, stabilizing NICD and enhancing NOTCH1 signaling. Integrating RBPJ-occupied genes in HG3 cells, RNA-Seq of USP28^WT/KO

SUBMITTER: Ehrmann AS 

PROVIDER: S-EPMC12310537 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature