{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:54:56Z","timestamp":1790708096585,"version":"4.1.0"},"reference-count":59,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T00:00:00Z","timestamp":1675814400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Bulgarian National Science Fund (BNSF)","award":["KP-06-H23\/12\/19.12.2018"],"award-info":[{"award-number":["KP-06-H23\/12\/19.12.2018"]}]},{"name":"Bulgarian National Science Fund (BNSF)","award":["DO1-395\/18.12.2020"],"award-info":[{"award-number":["DO1-395\/18.12.2020"]}]},{"name":"Bulgarian National Science Fund (BNSF)","award":["DO1-278\/14.12.2022"],"award-info":[{"award-number":["DO1-278\/14.12.2022"]}]},{"name":"National University Complex for Biomedical and Applied Research with participation in BBMRI-ERIC, NUCBPI-BBMRI.BG","award":["KP-06-H23\/12\/19.12.2018"],"award-info":[{"award-number":["KP-06-H23\/12\/19.12.2018"]}]},{"name":"National University Complex for Biomedical and Applied Research with participation in BBMRI-ERIC, NUCBPI-BBMRI.BG","award":["DO1-395\/18.12.2020"],"award-info":[{"award-number":["DO1-395\/18.12.2020"]}]},{"name":"National University Complex for Biomedical and Applied Research with participation in BBMRI-ERIC, NUCBPI-BBMRI.BG","award":["DO1-278\/14.12.2022"],"award-info":[{"award-number":["DO1-278\/14.12.2022"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The prognosis for patients with relapsed childhood acute lymphoblastic leukaemia (cALL) remains poor. The main reason for treatment failure is drug resistance, most commonly to glucocorticoids (GCs). The molecular differences between prednisolone-sensitive and -resistant lymphoblasts are not well-studied, thereby precluding the development of novel and targeted therapies. Therefore, the aim of this work was to elucidate at least some aspects of the molecular differences between matched pairs of GC-sensitive and -resistant cell lines. To address this, we carried out an integrated transcriptomic and metabolomic analysis, which revealed that lack of response to prednisolone may be underpinned by alterations in oxidative phosphorylation, glycolysis, amino acid, pyruvate and nucleotide biosynthesis, as well as activation of mTORC1 and MYC signalling, which are also known to control cell metabolism. In an attempt to explore the potential therapeutic effect of inhibiting one of the hits from our analysis, we targeted the glutamine-glutamate-\u03b1-ketoglutarate axis by three different strategies, all of which impaired mitochondrial respiration and ATP production and induced apoptosis. Thereby, we report that prednisolone resistance may be accompanied by considerable rewiring of transcriptional and biosynthesis programs. Among other druggable targets that were identified in this study, inhibition of glutamine metabolism presents a potential therapeutic approach in GC-sensitive, but more importantly, in GC-resistant cALL cells. Lastly, these findings may be clinically relevant in the context of relapse\u2014in publicly available datasets, we found gene expression patterns suggesting that in vivo drug resistance is characterised by similar metabolic dysregulation to what we found in our in vitro model.<\/jats:p>","DOI":"10.3390\/ijms24043378","type":"journal-article","created":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T04:21:59Z","timestamp":1675830119000},"page":"3378","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Targeting Glutaminolysis Shows Efficacy in Both Prednisolone-Sensitive and in Metabolically Rewired Prednisolone-Resistant B-Cell Childhood Acute Lymphoblastic Leukaemia Cells"],"prefix":"10.3390","volume":"24","author":[{"given":"Yordan","family":"Sbirkov","sequence":"first","affiliation":[{"name":"Department of Medical Biology, Medical University of Plovdiv, 4000 Plovdiv, Bulgaria"},{"name":"Research Institute at Medical University of Plovdiv (RIMU), 4000 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bozhidar","family":"Vergov","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Medical University of Plovdiv, 4000 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasil","family":"Dzharov","sequence":"additional","affiliation":[{"name":"Research Institute at Medical University of Plovdiv (RIMU), 4000 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tino","family":"Schenk","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Clinic of Internal Medicine II, Jena University Hospital, 07743 Jena, Germany"},{"name":"Institute of Molecular Cell Biology, Jena University Hospital, 07745 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Petrie","sequence":"additional","affiliation":[{"name":"School of Medicine, Faculty of Health Sciences and Wellbeing, University of Sunderland, Sunderland SR1 3SD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1501-0175","authenticated-orcid":false,"given":"Victoria","family":"Sarafian","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Medical University of Plovdiv, 4000 Plovdiv, Bulgaria"},{"name":"Research Institute at Medical University of Plovdiv (RIMU), 4000 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Malczewska, M., Kosmider, K., Bednarz, K., Ostapinska, K., Lejman, M., and Zawitkowska, J. 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