Figure 4.

In vitro response to BH3-mimetics in pediatric ALL xenografts. (A) Summary of the mean venetoclax LC₅₀ at 48 hours of each xenograft determined by AlamarBlue assay. Data are segregated by venetoclax in vivo response. Bar represents the median LC₅₀ of each cohort. Groups compared by Mann-Whitney test. (B) ALL xenografts cocultured with hTERT-MSCs were treated (concentration range 1 nM-4 μM) with navitoclax (n = 24), venetoclax (n = 24), A-1113567 (n = 23), or A-1155463 (n = 24) alone, or an equimolar 50:50 mixture of venetoclax and A-1155463 (n = 24). Viability was evaluated using propidium iodide exclusion by flow cytometry, and LC₅₀s calculated by nonlinear regression in Graphpad Prism are summarized here. A range rather than scale is depicted for LC₅₀ > 10 μM, as these correspond to extrapolated rather than measured values. Wilcoxon matched-pairs signed rank test was used for statistical comparison between groups. P values are represented as follows: *P ≤ .05; **P ≤ .01; ***P ≤ .001; ****P ≤ .0001. (C) Sensitivity to navitoclax correlates significantly with sensitivity to venetoclax alone or a 50:50 mixture of venetoclax and A-1155463, but not A-1155463 alone. A-1155463 LC₅₀ could not be calculated for the 2 samples with the highest navitoclax LC₅₀. Pearson correlation coefficients are listed. (D) Sensitivity to navitoclax, venetoclax, A-1113567, or A-1155463 alone, or the venetoclax and A-1155463 50:50 mixture, by ALL subtype. (E) In MLLr-ALL, sensitivity to navitoclax correlates strongly with venetoclax sensitivity.