Functional genome-wide CRISPR screen identifies PIK3R1 as being associated with resistance to Notch inhibition and druggable candidate pathways for combination therapies in T-ALL. (A) Schematic representation of the genome-wide LoF CRISPR screen using DND-41 T-ALL cells. (B) Volcano plots depicting genes targeted by sgRNAs that were negatively or positively selected, comparing GSI vs DMSO treatment. Red, adjusted P < .01 and log₂ fold change (FC) > 0.6; blue, adjusted P < .01 and log₂FC < −0.6. (C) Volcano plots showing genes targeted by sgRNAs that were negatively or positively selected, comparing CB-103 vs DMSO treatment. Red, adjusted P < .01 and log₂FC > 0.6; blue, adjusted P < .01 and log₂FC < −0.6. (D) Robust rank aggregation (RRA) plots displaying the top 10 enriched sgRNAs, comparing GSI vs DMSO treatment. (E) RRA plots displaying top enriched sgRNAs, comparing CB-103 vs DMSO treatment.