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Targeting Glutaminolysis Shows Efficacy in Both Prednisolone-Sensitive and in Metabolically Rewired Prednisolone-Resistant B-Cell Childhood Acute Lymphoblastic Leukaemia Cells

Sbirkov, Yordan, Vergov, Bozhidar, Dzharov, Vasil, Schenk, Tino, Petrie, Kevin and Sarafian, Victoria (2023) Targeting Glutaminolysis Shows Efficacy in Both Prednisolone-Sensitive and in Metabolically Rewired Prednisolone-Resistant B-Cell Childhood Acute Lymphoblastic Leukaemia Cells. International Journal of Molecular Sciences, 24 (4). pp. 1-15. ISSN 1422-0067

Item Type: Article

Abstract

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-α-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—in 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.

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More Information

Uncontrolled Keywords: childhood ALL; metabolism; metabolomics; glutaminolysis; glutamine; EGCG (epigallocatechin gallate); V-9302; glucocorticoids; prednisolone; resistance
Depositing User: Kevin Petrie

Identifiers

Item ID: 15786
Identification Number: https://doi.org/10.3390/ijms24043378
ISSN: 1422-0067
URI: http://sure.sunderland.ac.uk/id/eprint/15786
Official URL: http://dx.doi.org/10.3390/ijms24043378

Users with ORCIDS

ORCID for Kevin Petrie: ORCID iD orcid.org/0000-0002-9805-9152

Catalogue record

Date Deposited: 15 Mar 2023 15:01
Last Modified: 20 Mar 2023 11:15

Contributors

Author: Kevin Petrie ORCID iD
Author: Yordan Sbirkov
Author: Bozhidar Vergov
Author: Vasil Dzharov
Author: Tino Schenk
Author: Victoria Sarafian

University Divisions

Faculty of Health Sciences and Wellbeing > School of Medicine

Subjects

Sciences > Biomedical Sciences
Sciences

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