The combination of MLN4924 and belinostat reduces tumor burden and significantly prolongs animal survival in a murine IV AML xenograft model carrying FLT3-ITD. NOD/SCID-γ (NSG) mice were inoculated via tail vein with 1 × 106 luciferase-labeled MV-4-11 cells harboring FLT3-ITD. Mice were randomized to 4 groups (n = 6 per group), and treatment was initiated 2 days after injection of tumor cells. MLN4924 (30 mg/kg) and belinostat (40 mg/kg) were administrated as described in Figure 6. Control animals were administered equal volumes of vehicle. (A) Tumor growth was monitored every other day after i.p. injection with 150 mg/kg luciferin using the IVIS 200 imaging system. Representative images of mice are shown. Red crossed lines indicate that mice were euthanized when humane end points were reached. (B) When mice were sacrificed, BM was harvested and subjected to FCM to determine the percentage of human CD45+ tumor cells in BM mononuclear cells. Two sets of representative data are shown. (C) Kaplan-Meier analysis was performed to analyze survival of animals (n = 6 per group). Inset, Median survival. Arrows indicate time when treatment began (day 2) and discontinued (day 50). D, Day when bone barrow was harvested after tumor cell inoculation; h, human; SSC, side scatter.
