Genome-wide CRISPR/Cas9 screens identify negative regulators of the mTORC1 pathway as key modulators of B-ALL cell sensitivity to dexamethasone. (A) Schematic of the CRISPR screen strategy used to identify regulators of GC-mediated signaling pathways. (B) Dot plots representing β-scores²⁶ of 19 114 genes in the presence or absence of dexamethasone. Genes whose β-scores show statistically significant changes upon drug treatment (false discovery rate [FDR] <0.1) are depicted in red. (C) CRISPR screen data showing gene-level ranking based on differential enrichment of sgRNAs by dexamethasone vs DMSO treatment. Normalized z score values were calculated using the DrugZ program.²⁸ Genes whose sgRNAs were significantly enriched by dexamethasone relative to DMSO treatment are shown in red, and those with sgRNAs significantly depleted are in blue. Genes associated with the GC signal pathway, mTORC1 pathway, Ras pathway, and autophagy are depicted in red, green, blue, and purple, respectively. (D) Venn diagram illustrating genes significantly enriched by dexamethasone relative to DMSO treatment (FDR <0.1) in NALM-6 and MUTZ-5 cells. Dex, dexamethasone.