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

In spite of the considerable progress in risk stratification and therapeutic regimens in childhood acute lymphoblastic leukaemia (cALL), which has led to cure rates of above 90%, prognosis for patients with relapsed disease remains poor. The main cause of therapy failure is drug resistance, most commonly to glucocorticoids (GCs). While alterations of cell metabolism in cALL are considered a hallmark of this malignancy as well, 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 investigate the biology of matched pairs of cell lines where GCs are effective and such with acquired lack of response to prednisolone. In order to address this, we took advantage of the molecular characterisation of an in vitro model of GC resistance we had previously developed. An integrated transcriptomic and metabolomic analysis revealed alterations in oxidative phosphorylation, glycolysis, amino acid, pyruvate and nucleotide biosynthesis, as well as activation of mTORC1 and MYC signaling, which are also known to control cell metabolism. In attempt to explore the potential therapeutic effect of inhibiting one of the hits from our analysis, we targeted the glutamine-glutamate-a-ketoglutarate axis by three different strategies, all of which impaired mitochondrial respiration and ATP production and induced apoptosis in both GC-sensitive and resistant cell lines. In summary, we report that prednisolone resistance may be accompanied by considerable rewiring of transcriptional and biosynthesis programs. We suggest that targeting glutamine metabolism presents a novel therapeutic approach in cALL. Overall design: Comparing biological triplicates of prednisolone sensitive (Sup-B15) and resistant (Sup-PR) childhood acute lymphoblastic leukaemia cells.