PXD058183-1

PXD058183 is an original dataset announced via ProteomeXchange.

Title	Chronic lymphocytic leukaemia cells exhibit functional heterogeneity in the unfolded protein response: a proteomic study
Description	Genomic, epigenomic, and transcriptomic studies have provided only a partial explanation of disease heterogeneity in chronic lymphocytic leukaemia (CLL). Since mRNA and protein expression do not always correlate, CLL heterogeneity was investigated using global cellular proteomics. Sequential Windowed Acquisition of All THeoretical fragments Mass Spectrometry (SWATH-MS) was applied to CLL samples obtained from patients undergoing initial treatment with fludarabine-containing chemoimmunotherapy. Two independent proteomic datasets were generated: one compared pre-treatment samples from 32 patients who achieved an optimal versus suboptimal therapy response; the other compared paired samples from 16 patients collected before treatment and at disease progression. eIF2 signalling, which is pivotal to the unfolded protein response (UPR), was identified by Ingenuity Pathway Analysis as the most enriched pathway in both datasets. eIF2 signalling was also identified as the top pathway in a fludarabine-resistant CLL cell line established from HG3 cells. Measurement of key components of the eIF2 signalling pathway by Western blotting showed 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 venetoclax. These findings provide the first evidence of functionally important heterogeneity in the UPR of CLL cells and, in doing so, illustrate the value of global cellular proteomics as an investigative tool in assessing differential patient response to therapy.
HostingRepository	PRIDE
AnnounceDate	2025-08-04
AnnouncementXML	Submission_2025-08-03_19:20:37.343.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Rosalind Jenkins
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	deamidated residue; iodoacetamide derivatized residue
Instrument	TripleTOF 6600

Revision	Datetime	Status	ChangeLog Entry
0	2024-11-22 14:10:23	ID requested
⏵ 1	2025-08-03 19:20:38	announced

Khan UT, Clarke K, Eagle G, Oates M, Hillmen P, Jayne S, Dyer MJS, Phipps A, Falciani F, Jenkins RE, Pettitt AR, The unfolded protein response influences therapy outcome and disease progression in chronic lymphocytic leukaemia. Sci Rep, 15(1):27496(2025) [pubmed]

10.1038/s41598-025-13495-1;

submitter keyword: Chronic lymphocytic leukaemia, disease heterogeneity, response to therapy, unfolded protein response

Rosalind Jenkins
contact affiliation	CDSS Bioanalytical Facility, Liverpool Shared Research Facilities, University of Liverpool
contact email	r.jenkins@liv.ac.uk
lab head
Rosalind Jenkins
contact affiliation	University of Liverpool
contact email	R.Jenkins@liv.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD058183
     1. Label: PRIDE project
     2. Name: Chronic lymphocytic leukaemia cells exhibit functional heterogeneity in the unfolded protein response: a proteomic study