Stable isotope tracing reveals glucose metabolism characteristics of drug-resistant B-cell acute lymphoblastic leukemia.

BACKGROUND

Adult B-cell acute lymphocytic leukemia (B-ALL) is a malignant hematologic tumor characterized by the uncontrolled proliferation of B-cell lymphoblasts in the bone marrow. Despite advances in treatment, including chemotherapy and consolidation therapy, many B-ALL patients experience unfavorable prognoses due to the development of drug resistance. The precise mechanisms governing chemotherapy resistance, particularly those related to metabolic reprogramming within tumors, remain inadequately elucidated.

RESULTS

Nalm6/DOX cells exhibited significantly elevated levels of glucose, pyruvate, alanine, glutamine, and glycine compared to Nalm6 cells. Conversely, reduced levels of citrate, acetate, and leucine were observed in Nalm6/DOX cells. Upon exposure to the culture medium supplemented with tracer 13C6-glucose, the Nalm6/DOX cells showed an increase in the abundance of 13C-alanine and a decrease in the levels of 13C-lactate, indicating impaired utilization of 13C-pyruvate. Combining β-chloro-alanine (ALTi) with DOX could decrease the drug resistance phenotype of Nalm6/DOX cells. The results demonstrated that glycolysis and tricarboxylic acid cycle were suppressed in Nalm6/DOX cells, while metabolic flux through the alanine and glutamine pathways was increased. Therefore, inhibition of alanine biosynthesis in Nalm6/DOX exhibits the potential to reverse drug resistance.

SIGNIFICANCE: A new insight into the impact of metabolism on chemotherapy resistance in B-ALL has been gained through the use of stable isotope resolved metabolomics based on nuclear magnetic resonance and ultra-performance liquid chromatography/tandem mass spectrometry. This provides promising ways for the development of innovative therapeutic strategies to alleviate drug resistance and relapse in affected patients.