Dysregulated arginine metabolism in precursor B-cell acute lymphoblastic leukemia in children: a metabolomic study

Abstract

BackgroundPrecursor B-cell acute lymphoblastic leukemia (B-ALL) is the most common cancers in children. Failure of induction chemotherapy is a major factor leading to relapse and death in children with B-ALL. Given the importance of altered metabolites in the carcinogenesis of pediatric B-ALL, studying the metabolic profile of children with B-ALL during induction chemotherapy and in different minimal residual disease (MRD) status may contribute to the management of pediatric B-ALL.MethodsWe collected paired peripheral blood plasma samples from children with B-ALL at pre- and post-induction chemotherapy and analyzed the metabolomic profiling of these samples by ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS). Healthy children were included as controls. We selected metabolites that were depleted in pediatric B-ALL and analyzed the concentrations in pediatric B-ALL samples. In vitro, we study the effects of the selected metabolites on the viability of ALL cell lines and the sensitivity to conventional chemotherapeutic agents in ALL cell lines.ResultsForty-four metabolites were identified with different levels between groups. KEGG pathway enrichment analyses revealed that dysregulated linoleic acid (LA) metabolism and arginine (Arg) biosynthesis were closely associated with pediatric B-ALL. We confirmed that LA and Arg were decreased in pediatric B-ALL samples. The treatment of LA and Arg inhibited the viability of NALM-6 and RS4;11 cells in a dose-dependent manner, respectively. Moreover, Arg increased the sensitivity of B-ALL cells to L-asparaginase and daunorubicin.ConclusionArginine increases the sensitivity of B-ALL cells to the conventional chemotherapeutic drugs L-asparaginase and daunorubicin. This may represent a promising therapeutic approach.