{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T22:33:20Z","timestamp":1784932400925,"version":"3.55.0"},"reference-count":61,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T00:00:00Z","timestamp":1753660800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T00:00:00Z","timestamp":1753660800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100015570","name":"Blood Cancer UK","doi-asserted-by":"publisher","award":["21021"],"award-info":[{"award-number":["21021"]}],"id":[{"id":"10.13039\/501100015570","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015570","name":"Blood Cancer UK","doi-asserted-by":"publisher","award":["21021"],"award-info":[{"award-number":["21021"]}],"id":[{"id":"10.13039\/501100015570","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["CRUKE\/09\/016"],"award-info":[{"award-number":["CRUKE\/09\/016"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","award":["07\/01\/38"],"award-info":[{"award-number":["07\/01\/38"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Leicester Experimental Cancer Medicine Centre","award":["ECMCQQR-2022\/100006"],"award-info":[{"award-number":["ECMCQQR-2022\/100006"]}]},{"name":"Leicester Experimental Cancer Medicine Centre","award":["ECMCQQR-2022\/100006"],"award-info":[{"award-number":["ECMCQQR-2022\/100006"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>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: \u2212\u00a06.245 and 3.317; <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001), as well as in a fludarabine-resistant CLL cell line established from HG3 cells (z-score: \u2212\u00a02.121; <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). Western blotting revealed that fludarabine-resistant HG3 cells expressed higher levels of PERK, which phosphorylates the regulatory eIF2\u03b1 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.<\/jats:p>","DOI":"10.1038\/s41598-025-13495-1","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T20:26:25Z","timestamp":1753734385000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The unfolded protein response influences therapy outcome and disease progression in chronic lymphocytic leukaemia"],"prefix":"10.1038","volume":"15","author":[{"given":"Umair Tahir","family":"Khan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"Clarke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gina","family":"Eagle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Oates","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Hillmen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Jayne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin J. S.","family":"Dyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Phipps","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Falciani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosalind E.","family":"Jenkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew R","family":"Pettitt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,28]]},"reference":[{"key":"13495_CR1","unstructured":"Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute. Cancer Stat Facts: Leukemia\u2014Chronic Lymphocytic Leukemia (CLL) \u2013\u20092022, https:\/\/seer.cancer.gov\/statfacts\/html\/clyl.html."},{"key":"13495_CR2","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1016\/S0140-6736(10)61381-5","volume":"376","author":"M Hallek","year":"2010","unstructured":"Hallek, M. et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 376, 1164\u20131174. https:\/\/doi.org\/10.1016\/S0140-6736(10)61381-5 (2010).","journal-title":"Lancet"},{"key":"13495_CR3","doi-asserted-by":"publisher","first-page":"4070","DOI":"10.1200\/JCO.2005.12.516","volume":"23","author":"W Wierda","year":"2005","unstructured":"Wierda, W. et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J. Clin. Oncol. 23, 4070\u20134078. https:\/\/doi.org\/10.1200\/JCO.2005.12.516 (2005).","journal-title":"J. Clin. Oncol."},{"key":"13495_CR4","doi-asserted-by":"publisher","unstructured":"Brown, J. R. The treatment of relapsed refractory chronic lymphocytic leukemia. Hematol. Am. Soc. Hematol. Educ. Program 2011, 110\u2013118 https:\/\/doi.org\/10.1182\/asheducation-2011.1.110 (2011).","DOI":"10.1182\/asheducation-2011.1.110"},{"key":"13495_CR5","doi-asserted-by":"publisher","first-page":"2589","DOI":"10.1182\/blood-2009-05-224071","volume":"114","author":"T Zenz","year":"2009","unstructured":"Zenz, T. et al. Detailed analysis of p53 pathway defects in fludarabine-refractory chronic lymphocytic leukemia (CLL): dissecting the contribution of 17p deletion, TP53 mutation, p53-p21 dysfunction, and miR34a in a prospective clinical trial. Blood 114, 2589\u20132597. https:\/\/doi.org\/10.1182\/blood-2009-05-224071 (2009).","journal-title":"Blood"},{"key":"13495_CR6","doi-asserted-by":"publisher","first-page":"e1001393","DOI":"10.1371\/journal.pgen.1001393","volume":"7","author":"A Ghazalpour","year":"2011","unstructured":"Ghazalpour, A. et al. Comparative analysis of proteome and transcriptome variation in mouse. PLoS Genet. 7, e1001393. https:\/\/doi.org\/10.1371\/journal.pgen.1001393 (2011).","journal-title":"PLoS Genet."},{"key":"13495_CR7","doi-asserted-by":"publisher","first-page":"1680","DOI":"10.1038\/s42255-021-00504-6","volume":"3","author":"Y Harnik","year":"2021","unstructured":"Harnik, Y. et al. Spatial discordances between mRNAs and proteins in the intestinal epithelium. Nat. Metab. 3, 1680\u20131693. https:\/\/doi.org\/10.1038\/s42255-021-00504-6 (2021).","journal-title":"Nat. Metab."},{"key":"13495_CR8","doi-asserted-by":"publisher","first-page":"1259038","DOI":"10.1126\/science.1259038","volume":"347","author":"M Jovanovic","year":"2015","unstructured":"Jovanovic, M. et al. Immunogenetics. Dynamic profiling of the protein life cycle in response to pathogens. Science 347, 1259038. https:\/\/doi.org\/10.1126\/science.1259038 (2015).","journal-title":"Science"},{"key":"13495_CR9","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1186\/s13059-015-0608-2","volume":"16","author":"YN Wei","year":"2015","unstructured":"Wei, Y. N. et al. Transcript and protein expression decoupling reveals RNA binding proteins and MiRNAs as potential modulators of human aging. Genome Biol. 16, 41. https:\/\/doi.org\/10.1186\/s13059-015-0608-2 (2015).","journal-title":"Genome Biol."},{"key":"13495_CR10","doi-asserted-by":"publisher","first-page":"2932","DOI":"10.1038\/s41598-021-82609-2","volume":"11","author":"GL Eagle","year":"2021","unstructured":"Eagle, G. L. et al. Assessing technical and biological variation in SWATH-MS-based proteomic analysis of chronic lymphocytic leukaemia cells. Sci. Rep. 11, 2932. https:\/\/doi.org\/10.1038\/s41598-021-82609-2 (2021).","journal-title":"Sci. Rep."},{"key":"13495_CR11","doi-asserted-by":"publisher","first-page":"1675","DOI":"10.1517\/14656566.2012.703653","volume":"13","author":"C Ujjani","year":"2012","unstructured":"Ujjani, C. & Cheson, B. D. Chronic lymphocytic leukemia: where are we and where are we going? Expert Opin. Pharmacother. 13, 1675\u20131677. https:\/\/doi.org\/10.1517\/14656566.2012.703653 (2012).","journal-title":"Expert Opin. Pharmacother"},{"key":"13495_CR12","doi-asserted-by":"publisher","unstructured":"McDermott, M. et al. In vitro development of chemotherapy and targeted therapy drug-resistant cancer cell lines: a practical guide with case studies. Front. Oncol. 4 https:\/\/doi.org\/10.3389\/fonc.2014.00040 (2014).","DOI":"10.3389\/fonc.2014.00040"},{"key":"13495_CR13","doi-asserted-by":"publisher","first-page":"7193","DOI":"10.1021\/jm300713s","volume":"55","author":"JM Axten","year":"2012","unstructured":"Axten, J. M. et al. Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-p yrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like Endoplasmic reticulum kinase (PERK). J. Med. Chem. 55, 7193\u20137207. https:\/\/doi.org\/10.1021\/jm300713s (2012).","journal-title":"J. Med. Chem."},{"key":"13495_CR14","unstructured":"Selleckchem : GSK2606414. https:\/\/www.selleckchem.com\/products\/gsk2606414.html."},{"key":"13495_CR15","doi-asserted-by":"publisher","first-page":"2136","DOI":"10.1038\/s41467-019-10167-3","volume":"10","author":"T Adomavicius","year":"2019","unstructured":"Adomavicius, T. et al. The structural basis of translational control by eIF2 phosphorylation. Nat. Commun. 10, 2136. https:\/\/doi.org\/10.1038\/s41467-019-10167-3 (2019).","journal-title":"Nat. Commun."},{"key":"13495_CR16","doi-asserted-by":"publisher","unstructured":"F\u00e9ral, K. et al. ER stress and unfolded protein response in leukemia: friend, foe, or both?? Biomolecules 11 https:\/\/doi.org\/10.3390\/biom11020199 (2021).","DOI":"10.3390\/biom11020199"},{"key":"13495_CR17","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1038\/35014014","volume":"2","author":"A Bertolotti","year":"2000","unstructured":"Bertolotti, A., Zhang, Y., Hendershot, L. M., Harding, H. P. & Ron, D. Dynamic interaction of bip and ER stress transducers in the unfolded-protein response. Nat. Cell. Biol. 2, 326\u2013332. https:\/\/doi.org\/10.1038\/35014014 (2000).","journal-title":"Nat. Cell. Biol."},{"key":"13495_CR18","doi-asserted-by":"publisher","unstructured":"Carrara, M., Prischi, F., Nowak, P. R., Kopp, M. C. & Ali, M. M. Noncanonical binding of bip ATPase domain to Ire1 and Perk is dissociated by unfolded protein CH1 to initiate ER stress signaling. Elife 4 https:\/\/doi.org\/10.7554\/eLife.03522 (2015).","DOI":"10.7554\/eLife.03522"},{"key":"13495_CR19","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1038\/nrm2199","volume":"8","author":"D Ron","year":"2007","unstructured":"Ron, D. & Walter, P. Signal integration in the Endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell. Biol. 8, 519\u2013529. https:\/\/doi.org\/10.1038\/nrm2199 (2007).","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"13495_CR20","doi-asserted-by":"publisher","first-page":"1389","DOI":"10.1172\/JCI16886","volume":"110","author":"RJ Kaufman","year":"2002","unstructured":"Kaufman, R. J. Orchestrating the unfolded protein response in health and disease. J. Clin. Invest. 110, 1389\u20131398. https:\/\/doi.org\/10.1172\/JCI16886 (2002).","journal-title":"J. Clin. Invest."},{"key":"13495_CR21","doi-asserted-by":"publisher","unstructured":"Siwecka, N. et al. Dual role of endoplasmic reticulum stress-mediated unfolded protein response signaling pathway in carcinogenesis. Int. J. Mol. Sci. 20 https:\/\/doi.org\/10.3390\/ijms20184354 (2019).","DOI":"10.3390\/ijms20184354"},{"key":"13495_CR22","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1038\/s41580-020-0250-z","volume":"21","author":"C Hetz","year":"2020","unstructured":"Hetz, C., Zhang, K. & Kaufman, R. J. Mechanisms, regulation and functions of the unfolded protein response. Nat. Rev. Mol. Cell. Biol. 21, 421\u2013438. https:\/\/doi.org\/10.1038\/s41580-020-0250-z (2020).","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"13495_CR23","doi-asserted-by":"publisher","first-page":"e374","DOI":"10.1371\/journal.pbio.0040374","volume":"4","author":"DT Rutkowski","year":"2006","unstructured":"Rutkowski, D. T. et al. Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins. PLoS Biol. 4, e374. https:\/\/doi.org\/10.1371\/journal.pbio.0040374 (2006).","journal-title":"PLoS Biol."},{"key":"13495_CR24","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/1752-0509-7-16","volume":"7","author":"K Erguler","year":"2013","unstructured":"Erguler, K., Pieri, M. & Deltas, C. A mathematical model of the unfolded protein stress response reveals the decision mechanism for recovery, adaptation and apoptosis. BMC Syst. Biol. 7, 16. https:\/\/doi.org\/10.1186\/1752-0509-7-16 (2013).","journal-title":"BMC Syst. Biol."},{"key":"13495_CR25","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1021\/pr100803b","volume":"10","author":"S Mactier","year":"2011","unstructured":"Mactier, S., Henrich, S., Che, Y., Kohnke, P. L. & Christopherson, R. I. Comprehensive proteomic analysis of the effects of purine analogs on human Raji B-cell lymphoma. J. Proteome Res. 10, 1030\u20131042. https:\/\/doi.org\/10.1021\/pr100803b (2011).","journal-title":"J. Proteome Res."},{"key":"13495_CR26","doi-asserted-by":"publisher","first-page":"2713","DOI":"10.1182\/blood-2010-03-275628","volume":"116","author":"E Rosati","year":"2010","unstructured":"Rosati, E. et al. Novel targets for Endoplasmic reticulum stress-induced apoptosis in B-CLL. Blood 116, 2713\u20132723. https:\/\/doi.org\/10.1182\/blood-2010-03-275628 (2010).","journal-title":"Blood"},{"key":"13495_CR27","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/j.trecan.2016.03.007","volume":"2","author":"H Urra","year":"2016","unstructured":"Urra, H., Dufey, E., Avril, T., Chevet, E. & Hetz, C. Endoplasmic reticulum stress and the hallmarks of cancer. Trends Cancer. 2, 252\u2013262. https:\/\/doi.org\/10.1016\/j.trecan.2016.03.007 (2016).","journal-title":"Trends Cancer"},{"key":"13495_CR28","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1158\/2159-8290.CD-13-0945","volume":"4","author":"YX Feng","year":"2014","unstructured":"Feng, Y. X. et al. Epithelial-to-mesenchymal transition activates PERK-eIF2alpha and sensitizes cells to Endoplasmic reticulum stress. Cancer Discov. 4, 702\u2013715. https:\/\/doi.org\/10.1158\/2159-8290.CD-13-0945 (2014).","journal-title":"Cancer Discov"},{"key":"13495_CR29","doi-asserted-by":"publisher","first-page":"3881","DOI":"10.1038\/onc.2010.153","volume":"29","author":"E Bobrovnikova-Marjon","year":"2010","unstructured":"Bobrovnikova-Marjon, E. et al. PERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage. Oncogene 29, 3881\u20133895. https:\/\/doi.org\/10.1038\/onc.2010.153 (2010).","journal-title":"Oncogene"},{"key":"13495_CR30","doi-asserted-by":"publisher","unstructured":"Wang, P. et al. The prognostic value of PERK in cancer and its relationship with immune cell infiltration. Front. Mol. Biosci. 8 https:\/\/doi.org\/10.3389\/fmolb.2021.648752 (2021).","DOI":"10.3389\/fmolb.2021.648752"},{"key":"13495_CR31","doi-asserted-by":"publisher","first-page":"2864","DOI":"10.3390\/cancers12102864","volume":"12","author":"T Bagratuni","year":"2020","unstructured":"Bagratuni, T. et al. Characterization of a PERK kinase inhibitor with Anti-Myeloma activity. Cancers 12, 2864 (2020).","journal-title":"Cancers"},{"key":"13495_CR32","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.nbd.2018.01.004","volume":"112","author":"G Mercado","year":"2018","unstructured":"Mercado, G. et al. Targeting PERK signaling with the small molecule GSK2606414 prevents neurodegeneration in a model of parkinson\u2019s disease. Neurobiol. Dis. 112, 136\u2013148. https:\/\/doi.org\/10.1016\/j.nbd.2018.01.004 (2018).","journal-title":"Neurobiol. Dis."},{"key":"13495_CR33","doi-asserted-by":"publisher","first-page":"986","DOI":"10.1046\/j.1365-2141.1999.01448.x","volume":"105","author":"AR Pettitt","year":"1999","unstructured":"Pettitt, A. R., Clarke, A. R., Cawley, J. C. & Griffiths, S. D. Purine analogues kill resting lymphocytes by p53-dependent and -independent mechanisms. Br. J. Haematol. 105, 986\u2013988. https:\/\/doi.org\/10.1046\/j.1365-2141.1999.01448.x (1999).","journal-title":"Br. J. Haematol."},{"key":"13495_CR34","first-page":"4187","volume":"60","author":"AR Pettitt","year":"2000","unstructured":"Pettitt, A. R., Sherrington, P. D. & Cawley, J. C. Role of poly(ADP-ribosyl)ation in the killing of chronic lymphocytic leukemia cells by purine analogues. Cancer Res. 60, 4187\u20134193 (2000).","journal-title":"Cancer Res."},{"key":"13495_CR35","doi-asserted-by":"publisher","unstructured":"Read, A. & Schroder, M. The unfolded protein response: an overview. Biology (Basel). 10. https:\/\/doi.org\/10.3390\/biology10050384 (2021).","DOI":"10.3390\/biology10050384"},{"key":"13495_CR36","doi-asserted-by":"publisher","first-page":"9750","DOI":"10.1158\/0008-5472.Can-07-2047","volume":"67","author":"CC Jiang","year":"2007","unstructured":"Jiang, C. C. et al. Inhibition of MEK sensitizes human melanoma cells to Endoplasmic reticulum stress-induced apoptosis. Cancer Res. 67, 9750\u20139761. https:\/\/doi.org\/10.1158\/0008-5472.Can-07-2047 (2007).","journal-title":"Cancer Res."},{"key":"13495_CR37","doi-asserted-by":"publisher","first-page":"20915","DOI":"10.1074\/jbc.M212328200","volume":"278","author":"RK Reddy","year":"2003","unstructured":"Reddy, R. K. et al. Endoplasmic reticulum chaperone protein GRP78 protects cells from apoptosis induced by topoisomerase inhibitors: role of ATP binding site in suppression of caspase-7 activation. J. Biol. Chem. 278, 20915\u201320924. https:\/\/doi.org\/10.1074\/jbc.M212328200 (2003).","journal-title":"J. Biol. Chem."},{"key":"13495_CR38","doi-asserted-by":"publisher","first-page":"3734","DOI":"10.1158\/0008-5472.Can-06-4594","volume":"67","author":"Y Fu","year":"2007","unstructured":"Fu, Y., Li, J. & Lee, A. S. GRP78\/BiP inhibits Endoplasmic reticulum BIK and protects human breast cancer cells against Estrogen starvation-induced apoptosis. Cancer Res. 67, 3734\u20133740. https:\/\/doi.org\/10.1158\/0008-5472.Can-06-4594 (2007).","journal-title":"Cancer Res."},{"key":"13495_CR39","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1016\/j.etap.2016.05.005","volume":"44","author":"JK Kim","year":"2016","unstructured":"Kim, J. K. et al. Endoplasmic reticulum stress induces 5-fluorouracil resistance in human colon cancer cells. Environ. Toxicol. Pharmacol. 44, 128\u2013133. https:\/\/doi.org\/10.1016\/j.etap.2016.05.005 (2016).","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"13495_CR40","doi-asserted-by":"publisher","first-page":"3888","DOI":"10.1111\/j.1582-4934.2009.00873.x","volume":"13","author":"J Wang","year":"2009","unstructured":"Wang, J. et al. Blockade of GRP78 sensitizes breast cancer cells to microtubules-interfering agents that induce the unfolded protein response. J. Cell. Mol. Med. 13, 3888\u20133897. https:\/\/doi.org\/10.1111\/j.1582-4934.2009.00873.x (2009).","journal-title":"J. Cell. Mol. Med."},{"key":"13495_CR41","doi-asserted-by":"publisher","first-page":"2601","DOI":"10.1016\/j.ajpath.2011.07.031","volume":"179","author":"A Mozos","year":"2011","unstructured":"Mozos, A. et al. The expression of the Endoplasmic reticulum stress sensor BiP\/GRP78 predicts response to chemotherapy and determines the efficacy of proteasome inhibitors in diffuse large b-cell lymphoma. Am. J. Pathol. 179, 2601\u20132610. https:\/\/doi.org\/10.1016\/j.ajpath.2011.07.031 (2011).","journal-title":"Am. J. Pathol."},{"key":"13495_CR42","doi-asserted-by":"publisher","first-page":"e41168","DOI":"10.7554\/eLife.41168","volume":"8","author":"M Vitale","year":"2019","unstructured":"Vitale, M. et al. Inadequate bip availability defines Endoplasmic reticulum stress. eLife 8, e41168. https:\/\/doi.org\/10.7554\/eLife.41168 (2019).","journal-title":"eLife"},{"key":"13495_CR43","doi-asserted-by":"publisher","first-page":"3101","DOI":"10.1182\/blood-2014-04-567198","volume":"124","author":"S Krysov","year":"2014","unstructured":"Krysov, S. et al. Stimulation of surface IgM of chronic lymphocytic leukemia cells induces an unfolded protein response dependent on BTK and SYK. Blood 124, 3101\u20133109. https:\/\/doi.org\/10.1182\/blood-2014-04-567198 (2014).","journal-title":"Blood"},{"key":"13495_CR44","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1002\/pros.23264","volume":"77","author":"J Liu","year":"2017","unstructured":"Liu, J. et al. Activation of UPR signaling pathway is associated with the malignant progression and poor prognosis in prostate cancer. Prostate 77, 274\u2013281. https:\/\/doi.org\/10.1002\/pros.23264 (2017).","journal-title":"Prostate"},{"key":"13495_CR45","doi-asserted-by":"crossref","unstructured":"Dudek, A. Z. et al. A multicenter, open-label, phase 1a study of HC-5404 in patients with advanced solid tumors. J. Clin. Oncol. 42, e15118\u2013e15118 (2024).","DOI":"10.1200\/JCO.2024.42.16_suppl.e15118"},{"key":"13495_CR46","doi-asserted-by":"publisher","DOI":"10.6084\/m9.figshare.4530893.v5","author":"The National Genomics Research and Healthcare Knowledgebase v5","year":"2019","unstructured":"The National Genomics Research and Healthcare Knowledgebase v5. Genomics Engl. https:\/\/doi.org\/10.6084\/m9.figshare.4530893.v5. (2019).","journal-title":"Genomics Engl."},{"key":"13495_CR47","unstructured":"NCRI. Establishing a resource for chronic lymphocytic leukaemia researchers. https:\/\/www.ncri.org.uk\/improving-access-to-chronic-lymphocytic-leukaemia-samples\/."},{"key":"13495_CR48","doi-asserted-by":"publisher","first-page":"D1539","DOI":"10.1093\/nar\/gkac1040","volume":"51","author":"EW Deutsch","year":"2023","unstructured":"Deutsch, E. W. et al. The proteomexchange consortium at 10 years: 2023 update. Nucleic Acids Res. 51, D1539\u2013d1548. https:\/\/doi.org\/10.1093\/nar\/gkac1040 (2023).","journal-title":"Nucleic Acids Res."},{"key":"13495_CR49","doi-asserted-by":"publisher","first-page":"D543","DOI":"10.1093\/nar\/gkab1038","volume":"50","author":"Y Perez-Riverol","year":"2022","unstructured":"Perez-Riverol, Y. et al. The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences. Nucleic Acids Res. 50, D543\u2013d552. https:\/\/doi.org\/10.1093\/nar\/gkab1038 (2022).","journal-title":"Nucleic Acids Res."},{"key":"13495_CR50","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/s41592-019-0638-x","volume":"17","author":"V Demichev","year":"2020","unstructured":"Demichev, V., Messner, C. B., Vernardis, S. I., Lilley, K. S. & Ralser, M. DIA-NN: neural networks and interference correction enable deep proteome coverage in high throughput. Nat. Methods. 17, 41\u201344. https:\/\/doi.org\/10.1038\/s41592-019-0638-x (2020).","journal-title":"Nat. Methods"},{"key":"13495_CR51","doi-asserted-by":"publisher","first-page":"2513","DOI":"10.1074\/mcp.M113.031591","volume":"13","author":"J Cox","year":"2014","unstructured":"Cox, J. et al. Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ. Mol. Cell. Proteom. 13, 2513\u20132526. https:\/\/doi.org\/10.1074\/mcp.M113.031591 (2014).","journal-title":"Mol. Cell. Proteom."},{"key":"13495_CR52","unstructured":"R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. https:\/\/www.R-project.org\/ (2019)."},{"key":"13495_CR53","doi-asserted-by":"publisher","first-page":"e10240","DOI":"10.15252\/msb.202110240","volume":"17","author":"J \u010cuklina","year":"2021","unstructured":"\u010cuklina, J. et al. Diagnostics and correction of batch effects in large-scale proteomic studies: a tutorial. Mol. Syst. Biol. 17, e10240. https:\/\/doi.org\/10.15252\/msb.202110240 (2021).","journal-title":"Mol. Syst. Biol."},{"key":"13495_CR54","unstructured":"\u010cuklina, J. (Thesis) Computational challenges in biomarker discovery from high-throughput proteomic data (2018)."},{"key":"13495_CR55","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","volume":"43","author":"ME Ritchie","year":"2015","unstructured":"Ritchie, M. E. et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47. https:\/\/doi.org\/10.1093\/nar\/gkv007 (2015).","journal-title":"Nucleic Acids Res."},{"key":"13495_CR56","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1093\/biostatistics\/kxv027","volume":"17","author":"V Nygaard","year":"2016","unstructured":"Nygaard, V., Rodland, E. A. & Hovig, E. Methods that remove batch effects while retaining group differences May lead to exaggerated confidence in downstream analyses. Biostatistics 17, 29\u201339. https:\/\/doi.org\/10.1093\/biostatistics\/kxv027 (2016).","journal-title":"Biostatistics"},{"key":"13495_CR57","doi-asserted-by":"publisher","first-page":"18","DOI":"10.4161\/onci.1.1.18400","volume":"1","author":"A Rosen","year":"2012","unstructured":"Rosen, A. et al. Lymphoblastoid cell line with B1 cell characteristics established from a chronic lymphocytic leukemia clone by in vitro EBV infection. Oncoimmunology 1, 18\u201327. https:\/\/doi.org\/10.4161\/onci.1.1.18400 (2012).","journal-title":"Oncoimmunology"},{"key":"13495_CR58","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/s0145-2126(98)00154-4","volume":"23","author":"A Stacchini","year":"1999","unstructured":"Stacchini, A. et al. MEC1 and MEC2: two new cell lines derived from B-chronic lymphocytic leukaemia in prolymphocytoid transformation. Leuk. Res. 23, 127\u2013136. https:\/\/doi.org\/10.1016\/s0145-2126(98)00154-4 (1999).","journal-title":"Leuk. Res."},{"key":"13495_CR59","first-page":"40","volume":"91","author":"A Zamo","year":"2006","unstructured":"Zamo, A. et al. Establishment of the MAVER-1 cell line, a model for leukemic and aggressive mantle cell lymphoma. Haematologica 91, 40\u201347 (2006).","journal-title":"Haematologica"},{"key":"13495_CR60","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1093\/bioinformatics\/btt703","volume":"30","author":"A Kramer","year":"2014","unstructured":"Kramer, A., Green, J., Pollard, J. Jr. & Tugendreich, S. Causal analysis approaches in ingenuity pathway analysis. Bioinformatics 30, 523\u2013530. https:\/\/doi.org\/10.1093\/bioinformatics\/btt703 (2014).","journal-title":"Bioinformatics"},{"key":"13495_CR61","doi-asserted-by":"publisher","first-page":"2448","DOI":"10.1002\/pmic.201600044","volume":"16","author":"D Pascovici","year":"2016","unstructured":"Pascovici, D., Handler, D. C., Wu, J. X. & Haynes, P. A. Multiple testing corrections in quantitative proteomics: A useful but blunt tool. Proteomics 16, 2448\u20132453. https:\/\/doi.org\/10.1002\/pmic.201600044 (2016).","journal-title":"Proteomics"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-13495-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-13495-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-13495-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T05:51:31Z","timestamp":1757310691000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-13495-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,28]]},"references-count":61,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["13495"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-13495-1","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,28]]},"assertion":[{"value":"26 March 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 July 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 July 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"UTK held a Fellowship that was partly funded by Eli Lilly, Novartis, Roche and UCB Pharma.AP has received research support\/funding from Celgene\/BMS, Gilead, GSK\/Novartis, Napp, Roche. All the remaining authors declare no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"27496"}}