Central role of the mTORC1 pathway in glucocorticoid activity against B-ALL cells

Glucocorticoids (GCs), such as dexamethasone and prednisone, are crucial components of B-cell precursor acute lymphoblastic leukemia (B-ALL) therapies. However, the molecular basis of GC-induced cell death remains elusive. Here we show that GC suppresses mTORC1 (mechanistic target of rapamycin complex 1) signaling and that, conversely, oncogenic activation of mTORC1 confers resistance to GC. Our genome-wide CRISPR/Cas9 dropout screens reveal that depletion of components of either the GATOR1 (Gap Activity TOward Rags 1) or TSC (Tuberous Sclerosis Complex) complexes, both negative regulators of mTORC1 signaling, significantly attenuates B-ALL cell sensitivity to dexamethasone. Dexamethasone primarily induces B-ALL cell death by downregulating mTORC1 activity, thus promoting autophagy and impairing protein synthesis. Dexamethasone treatment failed to suppress mTORC1 activity in B-ALL cells expressing mutant glucocorticoid receptors lacking DNA-binding capacity, suggesting that dexamethasone transcriptionally represses mTORC1 activity. RNA-sequencing analysis identified multiple dexamethasone target genes that negatively regulate mTORC1 activity. Our findings suggest that GC sensitivity is significantly influenced by oncogenic stimuli and/or growth factors that activate the PI3K-AKT-mTORC1 pathway. This is consistent with the frequent GC resistance found in Ph and Ph-like ALLs.