USP7 inhibits FOXO1 activity in chronic lymphocytic leukaemia cells enhancing cell survival.
- 1School of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, UK.
- 2NHS Greater Glasgow & Clyde Royal Alexandra Hospital, Paisley, UK.
- 3NHS Greater Glasgow & Clyde Queen Elizabeth University Hospital, UK.
Abstract
Signals emanating from the B cell receptor (BCR) are vital for driving cell survival and proliferation in chronic lymphocytic leukaemia (CLL). BCR-mediated signals in CLL cells promote nuclear exclusion and inactivation of the transcription factor forkhead box protein O1 (FOXO1) and transient upregulation of FOXO1 expression. To investigate the mechanisms that regulate FOXO1 inactivation, we focused on the role of deubiquitinase (DUB) family proteins. Stratifying expression of individual DUB proteins, we established that ubiquitin-specific protease 7 (USP7), USP8, USP9x, USP10 and USP14 are significantly upregulated compared to healthy B cells. USP7 interacts with FOXO1 in primary CLL cells, suggesting that modulation of USP7 activity may impact FOXO1 function. Using selective USP7 inhibitors, P5091 and HBX19818, or USP7 knockdown, combined with ibrutinib, we demonstrated enhanced FOXO1 nuclear localisation over ibrutinib alone and increased FOXO1 activity, leading to modulation of selected FOXO target genes. This resulted in reduced CLL cell viability and enhanced cell cycle arrest in MEC1 cells, largely reversed by FOXO1 knockdown. These findings suggest that dual targeting of BCR signalling and USP7 activity can harness FOXO1-mediated anti-tumour activity and may represent a novel therapeutic approach for CLL treatment.
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BibTeX
@article{almuhanna2026usp7,
title = {{USP7 inhibits FOXO1 activity in chronic lymphocytic leukaemia cells enhancing cell survival.}},
author = {Hassan N B Almuhanna and Jodie Hay and Michael W Moles and Lucy Clarke and Jennifer Cassels and Alison Sefcick and Alison M McCaig and Heather G Jørgensen and Alison M Michie},
journal = {Molecular oncology},
year = {2026},
month = oct,
doi = {10.1002/1878-0261.70350},
url = {https://europepmc.org/article/MED/42904581},
note = {CC BY},
}
RIS
TY - JOUR
TI - USP7 inhibits FOXO1 activity in chronic lymphocytic leukaemia cells enhancing cell survival.
AU - Hassan N B Almuhanna
AU - Jodie Hay
AU - Michael W Moles
AU - Lucy Clarke
AU - Jennifer Cassels
AU - Alison Sefcick
AU - Alison M McCaig
AU - Heather G Jørgensen
AU - Alison M Michie
PY - 2026
DA - 2026/10/21
JO - Molecular oncology
DO - 10.1002/1878-0261.70350
UR - https://europepmc.org/article/MED/42904581
AB - Signals emanating from the B cell receptor (BCR) are vital for driving cell survival and proliferation in chronic lymphocytic leukaemia (CLL). BCR-mediated signals in CLL cells promote nuclear exclusion and inactivation of the transcription factor forkhead box protein O1 (FOXO1) and transient upregulation of FOXO1 expression. To investigate the mechanisms that regulate FOXO1 inactivation, we focused on the role of deubiquitinase (DUB) family proteins. Stratifying expression of individual DUB proteins, we established that ubiquitin-specific protease 7 (USP7), USP8, USP9x, USP10 and USP14 are significantly upregulated compared to healthy B cells. USP7 interacts with FOXO1 in primary CLL cells, suggesting that modulation of USP7 activity may impact FOXO1 function. Using selective USP7 inhibitors, P5091 and HBX19818, or USP7 knockdown, combined with ibrutinib, we demonstrated enhanced FOXO1 nuclear localisation over ibrutinib alone and increased FOXO1 activity, leading to modulation of selected FOXO target genes. This resulted in reduced CLL cell viability and enhanced cell cycle arrest in MEC1 cells, largely reversed by FOXO1 knockdown. These findings suggest that dual targeting of BCR signalling and USP7 activity can harness FOXO1-mediated anti-tumour activity and may represent a novel therapeutic approach for CLL treatment.
SN - 1574-7891
SN - 1878-0261
ER -