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

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Affiliations

  • 1. Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
      Authors
    • Khan UT 1
    • Eagle G 1
    • Oates M 1
    • Pettitt AR 1
    (4 authors)
  • 2. Computational Biology Facility, University of Liverpool, Liverpool, UK.
      Authors
    • Clarke K 2
    • Falciani F 2
    (2 authors)
  • 3. Leeds Cancer Centre, Leeds Teaching Hospitals Trust, Leeds, UK.
      Authors
    • Hillmen P 3
    (1 author)
  • 4. Leicester Cancer Research Centre, The Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, UK.
      Authors
    • Jayne S 4
    • Dyer MJS 4
    (2 authors)
  • 5. PRED Innovation Centre Welwyn, Roche Products, Shire Park, Welwyn Garden City, Herts, UK.
      Authors
    • Phipps A 5
    (1 author)
    • Show all (6)

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Scientific Reports, 28 Jul 2025, 15(1):27496
https://doi.org/10.1038/s41598-025-13495-1 PMID: 40721481 PMCID: PMC12304208

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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.

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    Funding 

    Funders who supported this work.

    Blood Cancer UK (1)

    Cancer Research UK (1)

    Leicester Experimental Cancer Medicine Centre (1)

    • Grant ID: ECMCQQR-2022/100006

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    National Institute for Health Research (NIHR) (1)

    National Institute for Health and Care Research (1)

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