Targeting Glutaminolysis Shows Efficacy in Both Prednisolone-Sensitive and in Metabolically Rewired Prednisolone-Resistant B-Cell Childhood Acute Lymphoblastic Leukaemia Cells.
Yordan SbirkovBozhidar VergovVasil DzharovTino SchenkKevin PetrieVictoria SarafianPublished in: International journal of molecular sciences (2023)
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.
Keyphrases
- induced apoptosis
- signaling pathway
- endoplasmic reticulum stress
- oxidative stress
- gene expression
- single cell
- liver failure
- amino acid
- respiratory failure
- rna seq
- cancer therapy
- dna methylation
- cell cycle arrest
- acute lymphoblastic leukemia
- transcription factor
- acute myeloid leukemia
- early life
- single molecule
- diffuse large b cell lymphoma
- cell death
- hodgkin lymphoma
- intensive care unit
- aortic dissection
- cell proliferation
- gas chromatography
- childhood cancer
- stem cells
- high resolution
- data analysis
- heat shock protein