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. 2023 Jun 27;7(12):2917-2923.
doi: 10.1182/bloodadvances.2022007728.

BH3 profiling identifies BCL-2 dependence in adult patients with early T-cell progenitor acute lymphoblastic leukemia

Elyse A Olesinski  1 , Karanpreet S Bhatia  2 , Aarthi N Mahesh  2 , Shazwina Rosli  2 , Jameelah S Mohamed  3 , Wei Y Jen  3 , Nitin Jain  4 , Jacqueline S Garcia  1 , Gee C Wong  5 , Melissa Ooi  3 , Anthony Letai  1 , Marina Konopleva  4 , Shruti Bhatt  2
Affiliations

BH3 profiling identifies BCL-2 dependence in adult patients with early T-cell progenitor acute lymphoblastic leukemia

Elyse A Olesinski et al. Blood Adv. .
No abstract available

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Conflict of interest statement

Conflict-of-interest disclosure: M.K. reports grants and/or other from AbbVie, F. Hoffman La-Roche, Stemline Therapeutics, Forty-Seven, Eli Lilly, Cellectis, Calithera, Ablynx, Agios, Ascentage, AstraZeneca, Reata Pharmaceutical, Rafael Pharmaceutical, Sanofi, Janssen, and Genentech. A.L. reports consultation and research support from AbbVie, Novartis, and AstraZeneca, and is an equity-holding member of the scientific advisory boards of Zentalis Pharmaceuticals, Flash Therapeutics, and Dialectic Therapeutics. J.S.G. received research funding from AbbVie, Genentech, Prelude, AstraZeneca, and Pfizer, and served on advisory boards for AbbVie, Genentech, Bristol Myers Squibb, and Servier. M.O. has served on advisory boards for Amgen, Pfizer, Janssen, and Bristol Myers Squibb. The remaining authors declare no competing financial interests.

Figures

Figure 1.
Figure 1.
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.
Figure 2.
Figure 2.
Adult T-ALL specimens are primarily dependent on BCL-2 and partially dependent on BCL-XL for survival. (A-B) FACS-based BH3 profiles obtained using the BAD (BCL-2 and BCL-XL dependence) and HRK (BCL-XL dependence) peptides. One-way ANOVA analysis of % cytochrome c release between BAD vs DMSO and HRK vs DMSO; BAD vs HRK. (C) Spearman correlation between % cytochrome c release for BAD vs HRK and BAD vs BAD-HRK. (D/E) 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, A-1331852 vs DMSO, venetoclax vs navitoclax, venetoclax vs A-1331852, and navitoclax vs A-1331852. (F) Cell death assays using annexin V in adult T-ALL primary samples treated with venetoclax, navitoclax, or A-1331852 for 8 hours. Refer to supplemental Figure 1 for the additional samples. Data are plotted as the percentage of live cells compared with DMSO controls. Mean ± SD of 3 replicates. (G) Dot plot of BAD peptide response vs HRK peptide response in adult ETP-ALL (green) and T-ALL (dark blue). Red indicates probable BCL-2 dependence and blue indicates probable BCL-XL dependence. (H) Clinical response timelines of patients M, O, N, 15, 19, and 20. (I) Proposed schematic for the prediction of venetoclax and navitoclax efficacy based on BCL-2 and BCL-XL dependence. Note: gating of adult T-ALL primary blast samples. Priming was normalized to that of DMSO. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001; CR, complete response; MRD, minimal residual disease; PR, partial response; UN, untreated; ns, no significance. (A,D) The dotted line represents the threshold for significant priming determined using DMSO ± 3xSD.
Figure 2.
Figure 2.
Adult T-ALL specimens are primarily dependent on BCL-2 and partially dependent on BCL-XL for survival. (A-B) FACS-based BH3 profiles obtained using the BAD (BCL-2 and BCL-XL dependence) and HRK (BCL-XL dependence) peptides. One-way ANOVA analysis of % cytochrome c release between BAD vs DMSO and HRK vs DMSO; BAD vs HRK. (C) Spearman correlation between % cytochrome c release for BAD vs HRK and BAD vs BAD-HRK. (D/E) 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, A-1331852 vs DMSO, venetoclax vs navitoclax, venetoclax vs A-1331852, and navitoclax vs A-1331852. (F) Cell death assays using annexin V in adult T-ALL primary samples treated with venetoclax, navitoclax, or A-1331852 for 8 hours. Refer to supplemental Figure 1 for the additional samples. Data are plotted as the percentage of live cells compared with DMSO controls. Mean ± SD of 3 replicates. (G) Dot plot of BAD peptide response vs HRK peptide response in adult ETP-ALL (green) and T-ALL (dark blue). Red indicates probable BCL-2 dependence and blue indicates probable BCL-XL dependence. (H) Clinical response timelines of patients M, O, N, 15, 19, and 20. (I) Proposed schematic for the prediction of venetoclax and navitoclax efficacy based on BCL-2 and BCL-XL dependence. Note: gating of adult T-ALL primary blast samples. Priming was normalized to that of DMSO. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001; CR, complete response; MRD, minimal residual disease; PR, partial response; UN, untreated; ns, no significance. (A,D) The dotted line represents the threshold for significant priming determined using DMSO ± 3xSD.
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