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 me...

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Detalles Bibliográficos
Autores: Ehrmann, Alena Sophie, Quijada-Álamo, Miguel, Close, Viola, Guo, Min, Carracoi, Valentina, Pérez-Carretero, Claudia, Corchete, Luis A., Friedrich, Tobias, Giaimo, Benedetto Daniele, Yosifov, Deyan Yordanov, Bloehdorn, Johannes, Rodríguez-Sánchez, Alberto, Tausch, Eugen, Schneider, Christof, Döhner, Hartmut, Kietzmann, Thomas, Borggrefe, Tilman, Stilgenbauer, Stephan, Oswald, Franz, Hernández, Jesús M., Mertens, Daniel
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:dnet:digitalcsic_::22ae6ea99978966c12dab0c0d4ea6b47
Acceso en línea:http://hdl.handle.net/10261/425931
https://api.elsevier.com/content/abstract/scopus_id/105007085107
Access Level:acceso abierto
Palabra clave:Cell signalling
Chronic lymphocytic leukaemia
Oncogenes
Targeted therapies
Descripción
Sumario: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 USP28WT/KO 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.

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