Adult ETP-ALL has increased dependency on BCL-2 rather than BCL-XL for survival. (A) Experimental schematic of the baseline BH3 profiling. Cytochrome c release was measured by gating on blasts. (B) Binding affinities of BH3 peptides (BAD and HRK) and BH3 mimetics (venetoclax, navitoclax, and A-1331852) for antiapoptotic proteins BCL-2 and BCL-XL. (C/D) FACS-based BH3 profiles for BAD (BCL-2 and BCL-XL dependence) and HRK (BCL-XL dependence). One-way analysis of variance (ANOVA) for % cytochrome c release between BAD vs DMSO and BAD vs HRK. (E) Spearman correlation between % cytochrome c release for BAD vs HRK and BAD vs BAD-HRK. Data is normalized to DMSO. (F-G) FACS-based BH3 profiles for venetoclax, navitoclax, and A-1331852. One-way ANOVA analysis for % cytochrome c release between venetoclax vs DMSO, navitoclax vs DMSO, and venetoclax vs navitoclax. (H) Cell death assays using annexin V in adult ETP-ALL samples treated with venetoclax, navitoclax, or A-1331852 for 8 hours. Data are plotted as the percentage of live cells compared with the DMSO controls. Note: gating of adult ETP-ALL primary blast samples. ∗ P < .05; ∗∗ P < .01; ∗∗∗ P < .001; ∗∗∗∗ P < .0001. UN, untreated; ns, no significance. (C,F) The dotted line represents the threshold for significant priming determined using DMSO ± 3xSD.