NOTCH1 signaling is dysregulated by loss of the deubiquitinase USP28 with del(11q), uncovering USP28 inhibition as novel therapeutic target in CLL
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<sup>WT/KO</sup> cells and gene expression from del(11q) CLL patients, we identified 15 NOTCH1 target genes specifically dysregulated by deletion of USP28 and del(11q) potentially influencing CLL pathogenesis. Pharmacological inhibition of USP28 with the small molecule AZ1 suppressed NOTCH1 activation in primary CLL cells. AZ1 combined with the BCL-2 inhibitor venetoclax reduced CLL cell viability, particularly in samples with high NOTCH1 activity. Our findings highlight USP28 as promising therapeutic target and provide a rationale for combined inhibition of USP28 and BCL-2 in CLL patients with active NOTCH1 signaling.
Authors
- Luís A. Corchete (ORCID: https://orcid.org/0000-0003-4577-8599)
- Viola Close
- Tobias Friedrich (ORCID: https://orcid.org/0000-0003-4014-8678)
- Stephan Stilgenbauer (ORCID: https://orcid.org/0000-0002-6830-9296)
- Eugen Tausch (ORCID: https://orcid.org/0000-0002-9503-1226)
- Alberto Rodríguez‐Sánchez (ORCID: https://orcid.org/0000-0002-7844-9655)
- Jesús María Hernández‐Rivas (ORCID: https://orcid.org/0000-0002-9661-9371)
- Tilman Borggrefe
- Thomas Kietzmann (ORCID: https://orcid.org/0000-0003-0242-8636)
- Johannes Bloehdorn (ORCID: https://orcid.org/0000-0003-1433-9702)
- Franz Oswald (ORCID: https://orcid.org/0000-0002-2923-5765)
- Benedetto Daniele Giaimo (ORCID: https://orcid.org/0000-0003-0384-325X)
- Miguel Quijada‐Álamo (ORCID: https://orcid.org/0000-0002-4831-4565)
- Claudia Pérez‐Carretero (ORCID: https://orcid.org/0000-0002-2089-2742)
- Alena Sophie Ehrmann
- Christof Schneider (ORCID: https://orcid.org/0000-0001-9719-7345)
- Deyan Yordanov Yosifov (ORCID: https://orcid.org/0000-0002-5473-4398)
- Hartmut Döhner (ORCID: https://orcid.org/0000-0003-2116-5536)
- Daniel Mertens (ORCID: https://orcid.org/0000-0003-0227-7188)
- Min Guo (ORCID: https://orcid.org/0000-0001-9801-7692)
- Valentina Carracoi
Institutions
- German Cancer Research Center (DE)
- Universität Ulm (DE)
- Justus-Liebig-Universität Gießen (DE)
- Heidelberg University (DE)
- Centro de Investigación del Cáncer (ES)
- University Hospital Ulm (DE)
- University of Oulu (FI)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Leukemia
- Published
- 2025-06-02
- DOI
- https://doi.org/10.1038/s41375-025-02632-4
- Citations
- 4
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 3.22
Funders
- European Commission
- Deutsche Forschungsgemeinschaft
- Jane ja Aatos Erkon Säätiö
- China Scholarship Council
- Deutsche Krebshilfe
- Sigrid Juséliuksen Säätiö
- Consejería de Educación, Junta de Castilla y León
- Universität Ulm
- Fundación Española de Hematología y Hemoterapia
- Centro de Investigación Biomédica en Red de Cáncer
- Junta de Castilla y León
- Instituto de Salud Carlos III
- European Regional Development Fund
- Biocenter, University of Oulu