The unfolded protein response influences therapy outcome and disease progression in chronic lymphocytic leukaemia.


Khan, Umair Tahir, Clarke, Kim, Eagle, Gina, Oates, Melanie, Hillmen, Peter, Jayne, Sandrine, Dyer, Martin JS, Phipps, Alex, Falciani, Francesco, Jenkins, Rosalind E ORCID: 0000-0002-3730-1136 et al (show 1 more authors) (2025) The unfolded protein response influences therapy outcome and disease progression in chronic lymphocytic leukaemia. Scientific reports, 15 (1). 27496-. ISSN 2045-2322, 2045-2322

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Abstract

Since genomics, epigenomics and transcriptomics have provided only a partial explanation of chronic lymphocytic leukaemia (CLL) heterogeneity, and since concordance between mRNA and protein expression is incomplete, we related the CLL proteome to clinical outcome. CLL samples from patients who received fludarabine-containing chemoimmunotherapy were analysed by mass spectrometry (SWATH-MS). One dataset compared pre-treatment samples associated with an optimal versus suboptimal response, while another compared paired samples collected before treatment and at disease progression. eIF2 signalling (pivotal to the unfolded protein response (UPR)), was identified as the most enriched pathway in both datasets (respective z-scores: - 6.245 and 3.317; p < 0.0001), as well as in a fludarabine-resistant CLL cell line established from HG3 cells (z-score: - 2.121; p < 0.0001). Western blotting revealed that fludarabine-resistant HG3 cells expressed higher levels of PERK, which phosphorylates the regulatory eIF2α subunit, and lower levels of BiP, an HSP70 molecular chaperone that inactivates PERK but preferentially binds to misfolded proteins during ER stress. The PERK inhibitor, GSK2606414, sensitised resistant, but not sensitive, HG-3 cells to fludarabine without affecting background cell viability or cytotoxicity induced by the BCL-2 inhibitor venetoclax. These findings identify the UPR as a novel determinant of therapy outcome and disease progression in CLL.

Item Type: Article
Uncontrolled Keywords: Cell Line, Tumor, Humans, Disease Progression, eIF-2 Kinase, Eukaryotic Initiation Factor-2, Vidarabine, Treatment Outcome, Drug Resistance, Neoplasm, Aged, Middle Aged, Female, Male, Leukemia, Lymphocytic, Chronic, B-Cell, Unfolded Protein Response
Divisions: Faculty of Health & Life Sciences
Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology
Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology (T&R Staff)
Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Molecular & Clinical Cancer Medicine
Faculty of Health & Life Sciences > Tech, Infrastructure & Env Directorate
Faculty of Health & Life Sciences > Tech, Infrastructure & Env Directorate > Liverpool Shared Research Facilities
Depositing User: Symplectic Admin
Date Deposited: 08 Dec 2025 16:36
Last Modified: 08 Dec 2025 16:36
DOI: 10.1038/s41598-025-13495-1
Open Access URL: https://doi.org/10.1038/s41598-025-13495-1
Related Websites:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3196017
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