Figure 5.

In vivo treatment of MLL-AF9 AMLs with daunorubicin in combination with ABT-737. Kaplan–Meier survival curves for mice transplanted with MLL-AF9 AMLs. 8–10-week-old Ly5.1 C57BL/6 mice (non-irradiated) were injected with 0.5 × 10⁶ bone marrow cells from sick secondary WT/MLL-AF9 or BH3-only gene KO/MLL-AF9 mice (three recipients per tumor per treatment arm) and treatment was started 3 days later: 5 mg/kg daunorubicin [D] intravenously on days 1, 4 and 9 and/or 75 mg/kg ABT-737 [737] intraperitoneally on days 1–5 and 8–12; controls received saline [S] and ABT-737 vehicle [V]. Transplanted mice were monitored daily for symptoms of AML and euthanized if morbidly ill or at the end of experiment (100 days post treatment start). A total of (a) 5 WT/MLL-AF9 AMLs (#1211, 1223, 1224, 1411 and 1414), (b) 4 bim^−/− MLL-AF9 AMLs (#1158, 1213, 1249 and 1250), (c) 4 puma^−/− MLL-AF9 AMLs (#1218, 1225, 1226 and 1229) and (d) 5 noxa^−/− MLL-AF9 AMLs (#1306,1308, 1309, 1310 and 1311) were tested (see also Supplementary Figure S8 for individual tumor results). Statistical significance was determined by Log-rank (Mantle-Cox) test. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. Daunorubicin treatment alone, or in combination with ABT-737, significantly prolonged survival of WT/MLL-AF9 and bim^−/−/MLL-AF9 AMLs compared with saline treatment (P<0.0001), puma^−/−/MLL-AF9 had significantly prolonged survival when treated with daunorubicin alone (P=0.0173) or with daunorubicin in combination with ABT-737 (P=0.0026), as did noxa^−/−/MLL-AF9 when treated with daunorubicin alone (P=0.0006) or in combination with ABT-737 (P=0.0001). For all genotypes there was no significant difference (P>0.5) in survival between daunorubicin treatment and treatment with the combination of daunorubicin and ABT-737