Figure 5
Figure 5. Venetoclax kills CLL cells, murine lymph node B cells, and RS4;11 human lymphoblast cell lines irrespective of TP53 deletion, mutation, or function. (A) For patient CLL samples, the 24-hour in vitro sensitivity to venetoclax did not differ based on del(17p) status (Student t test P = .44). Deletion 17p was detected by fluorescence in situ hybridization in 18 of 55 samples; the median percentage of del(17p) cells was 44.5% (range 7.5% to 95%) in those samples. (B) For murine lymph node B cells, the concentration-response curves for venetoclax are plotted for isogenic Trp53 wild-type (blue; WT) and Trp53−/− (red; p53KO) mice in the left panel, and for nutlin-3a in the right panel. All cells were incubated for 24 hours. n = 3 independent experiments. p53KO, p53 knockout. (C) For RS4;11 human B-cell lymphoblast cell lines, the concentration-response curves for venetoclax (left panel; 24 hour incubation) are plotted for TP53 wild-type cell lines (blue; Control) bearing a nontargeting sGuide and TP53-deficient cells (red; sgTP53) bearing a TP53targeting sGuide (see “Methods”). Loss of TP53 expression was confirmed by western blot (supplemental Figure 4). The concentration-response curves for nutlin-3a after a 3-day incubation are shown in the right panel. n = 5 independent experiments of pools of cells. (D) For patient CLL samples, the 24-hour in vitro sensitivity to venetoclax of CLL for 31 patients did not differ between samples with both del(17p) and TP53 mutation (n = 11) compared with those with neither del(17p) nor TP53 mutation (n = 20; unpaired Student t test P = .40). Del(17p) was present in a median 52.5% (range 24% to 82%) of CLL cells in the double detected group. Det, detected; mut, mutated. (E) The 72-hour in vitro sensitivity of CLL to nutlin-3a for 17 patients differed between those with both del(17p) and TP53 mutation (n = 5) and those with neither del(17p) nor TP53 mutation (n = 12; unpaired Student t test P < .0001). Del(17p) was present in a median 52.5% (range 26.5% to 58%) of CLL cells in the double detected group.

Venetoclax kills CLL cells, murine lymph node B cells, and RS4;11 human lymphoblast cell lines irrespective of TP53 deletion, mutation, or function. (A) For patient CLL samples, the 24-hour in vitro sensitivity to venetoclax did not differ based on del(17p) status (Student t test P = .44). Deletion 17p was detected by fluorescence in situ hybridization in 18 of 55 samples; the median percentage of del(17p) cells was 44.5% (range 7.5% to 95%) in those samples. (B) For murine lymph node B cells, the concentration-response curves for venetoclax are plotted for isogenic Trp53 wild-type (blue; WT) and Trp53−/− (red; p53KO) mice in the left panel, and for nutlin-3a in the right panel. All cells were incubated for 24 hours. n = 3 independent experiments. p53KO, p53 knockout. (C) For RS4;11 human B-cell lymphoblast cell lines, the concentration-response curves for venetoclax (left panel; 24 hour incubation) are plotted for TP53 wild-type cell lines (blue; Control) bearing a nontargeting sGuide and TP53-deficient cells (red; sgTP53) bearing a TP53targeting sGuide (see “Methods”). Loss of TP53 expression was confirmed by western blot (supplemental Figure 4). The concentration-response curves for nutlin-3a after a 3-day incubation are shown in the right panel. n = 5 independent experiments of pools of cells. (D) For patient CLL samples, the 24-hour in vitro sensitivity to venetoclax of CLL for 31 patients did not differ between samples with both del(17p) and TP53 mutation (n = 11) compared with those with neither del(17p) nor TP53 mutation (n = 20; unpaired Student t test P = .40). Del(17p) was present in a median 52.5% (range 24% to 82%) of CLL cells in the double detected group. Det, detected; mut, mutated. (E) The 72-hour in vitro sensitivity of CLL to nutlin-3a for 17 patients differed between those with both del(17p) and TP53 mutation (n = 5) and those with neither del(17p) nor TP53 mutation (n = 12; unpaired Student t test P < .0001). Del(17p) was present in a median 52.5% (range 26.5% to 58%) of CLL cells in the double detected group.

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