Metabolic reprogramming of acute lymphoblastic leukemia cells in response to glucocorticoid treatment

Area of Science:

• Biochemistry
• Cell Biology
• Oncology

Background:

• Glucocorticoids (GCs) are vital in treating childhood acute lymphoblastic leukemia (ALL).
• The precise mechanisms of GC-induced ALL cell death, particularly the role of metabolic reprogramming, remain unclear.
• GCs inhibit glucose uptake and metabolism in ALL cells, but this alone doesn't fully explain autophagy and cell death induction.

Purpose of the Study:

• To elucidate the detailed metabolic effects of GCs on ALL cells.
• To investigate the link between metabolic reprogramming, autophagy, and GC-induced cell death in ALL.
• To explore the role of glutamine synthesis in GC response and potential resistance mechanisms in ALL.

Main Methods:

• Parallel time-course proteomics, metabolomics, and isotope-tracing studies were employed.
• Analysis of metabolic shifts including nucleotide synthesis, polyamine synthesis, and phosphatidylcholine synthesis.
• Investigation of glucose and glutamine metabolism, including their entry into the TCA cycle.

Main Results:

• GCs suppressed glycolysis and the entry of glucose and glutamine into the TCA cycle.
• Nucleotide synthesis decreased, while nucleobases accumulated; polyamine synthesis was inhibited; phosphatidylcholine synthesis increased.
• Glucocorticoid treatment robustly increased glutamine-ammonia ligase (GLUL) expression and cellular glutamine content, indicating induced glutamine synthesis.

Conclusions:

• GCs induce metabolic changes including growth arrest, autophagy, and catabolism preceding apoptosis in ALL cells.
• Induced glutamine synthesis, similar to nutrient-starved muscle, appears to influence autophagy and potentially cell death.
• Modulating glutamine synthesis impacts autophagosome content and cell viability, offering insights into GC mechanisms and resistance in ALL.