Figure 5.
TP53 or BAX silencing impaired response to BH3 mimetics combination. (A) Combination of S63845 and venetoclax was synergistic in TP53+/+ and TP53−/− NCI-H929 and XG7 clones. Clones were cultured for 24 hours with increasing concentrations of S63845 and venetoclax as indicated in the figure. Bliss scores were calculated using SynergyFinder (https://synergyfinder.fimm.fi/). The figure represents the mean of 3 independent experiments. (B) TP53 and BAX controlled the response to BH3 mimetics combination. TP53+/+ (n = 3) and TP53−/− (n = 3) XG7 and NCI-H929 clones as well as BAX−/− (n = 3) and BAK1−/− (n = 3) NCI-H929 clones were cultured for 24 hours with 20 nM (XG7) or 10 nM (NCI-H929) S63845 and/or 300 nM venetoclax, and cell death was assessed using flow cytometry. Statistical analyses were performed using the Mann-Whitney U or Wilcoxon matched pairs signed-rank tests. (C) Gain of 1q21, but not del17p, affected the response to S63845. Response to 25 nM S63845 or 300 nM venetoclax was assessed in 71 myeloma samples, characterized by FISH for both 1q21 gain and del17p (Table 2). The graphs represent cell death induced by each BH3 mimetic in function of 1q21 gain or del17p. Statistical analyses were performed using the Mann-Whitney U test. (D) Deletion of 17p had a trend to decrease the synergy between S63845 and venetoclax. The graphs represent cell death induced by 25 nM S63845 combined with 300 nM venetoclax depending on 1q gain or del17p (left and middle), and the difference between observed cell death (25 nM S63845 combined with 300 nM venetoclax) minus expected cell death (sum of cell death induced by 25 nM S63845 and by 300 nM venetoclax), depending on del17p. Cell death was assessed after 24 hours using flow cytometry. Statistical analyses were performed using the Mann-Whitney U test. ∗∗∗∗P < .0001; ∗∗∗P < .001; ∗∗P < .01; ∗P < .05.

TP53 or BAX silencing impaired response to BH3 mimetics combination. (A) Combination of S63845 and venetoclax was synergistic in TP53+/+ and TP53−/− NCI-H929 and XG7 clones. Clones were cultured for 24 hours with increasing concentrations of S63845 and venetoclax as indicated in the figure. Bliss scores were calculated using SynergyFinder (https://synergyfinder.fimm.fi/). The figure represents the mean of 3 independent experiments. (B) TP53 and BAX controlled the response to BH3 mimetics combination. TP53+/+ (n = 3) and TP53−/− (n = 3) XG7 and NCI-H929 clones as well as BAX−/− (n = 3) and BAK1−/− (n = 3) NCI-H929 clones were cultured for 24 hours with 20 nM (XG7) or 10 nM (NCI-H929) S63845 and/or 300 nM venetoclax, and cell death was assessed using flow cytometry. Statistical analyses were performed using the Mann-Whitney U or Wilcoxon matched pairs signed-rank tests. (C) Gain of 1q21, but not del17p, affected the response to S63845. Response to 25 nM S63845 or 300 nM venetoclax was assessed in 71 myeloma samples, characterized by FISH for both 1q21 gain and del17p (Table 2). The graphs represent cell death induced by each BH3 mimetic in function of 1q21 gain or del17p. Statistical analyses were performed using the Mann-Whitney U test. (D) Deletion of 17p had a trend to decrease the synergy between S63845 and venetoclax. The graphs represent cell death induced by 25 nM S63845 combined with 300 nM venetoclax depending on 1q gain or del17p (left and middle), and the difference between observed cell death (25 nM S63845 combined with 300 nM venetoclax) minus expected cell death (sum of cell death induced by 25 nM S63845 and by 300 nM venetoclax), depending on del17p. Cell death was assessed after 24 hours using flow cytometry. Statistical analyses were performed using the Mann-Whitney U test. ∗∗∗∗P < .0001; ∗∗∗P < .001; ∗∗P < .01; ∗P < .05.

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