Figure 2.
Synergistic effects of TGN and VEN in vitro and in vivo. (A) Synergistic effect of TGN and VEN on LSC-enriched AML blasts. Primary CD34+CD38– AML blasts (1 × 105 cells per mL, n = 3) were treated with indicated concentration of TGN and VEN. Levels of cell proliferation (left) and apoptosis (right) were evaluated, and synergy score of the drug combination was calculated. Max synergy score: 48.957 (left) and 53.912 (right). (B-E) Synergistic effects of TGN and VEN on FAO/OXPHOS levels, mitochondrial fission, apoptosis, and DNA fragmentation of LSC-enriched AML blasts. Primary CD34+CD38– AML blasts (n = 4) were treated with DMSO (VEH), TGN (1 μM), VEN (20 nM), or combination of TGN and VEN for 24 hours. (B) FAO levels. (C) OXPHOS levels. (D) Mitochondria length. Left, represented TEM images. Right, quantification of mitochondria length. (E) Levels of apoptosis (left) and DNA fragmentation (right). (F-G) Synergistic effects of TGN and VEN on MllPTD/WT/Flt3ITD/ITD AML mouse model. (F) Experimental design for TGN and VEN combined treatment. Normal B6 WT recipients were IV injected with 0.5 × 106 MllPTD/WT/Flt3ITD/ITD BM MNCs. The transplanted mice were then randomly divided into 4 groups (n = 10 per group) and treated with either VEH, TGN (75 mg/kg, once a day, oral gavage, 21 days), VEN (50 mg/kg, once a day, oral gavage, 21 days) or TGN/VEN at the same doses of single agents. On day 21, 106 BM MNCs cells from each treatment group were harvested for secondary transplant. (G) Left, Kaplan–Meier survival curve of primary transplanted leukemic mice treated with VEH (purple line, MS 55 days), VEN (green line, MS 55 days), TGN (blue line, MS 67 days), or TGN/VEN (red line, MS 75 days). Right, Kaplan–Meier survival curve of secondary transplanted leukemic mice treated with VEH (purple line, MS 25 days), VEN (green line, MS 25.5 days), TGN (blue line, MS 33 days), or TGN/VEN (red line, MS 42 days). (H-I) Synergistic effects of TGN and VEN on FLT3-WT PDX AML model. (H) Experimental design for TGN and VEN combined treatment. hCD45+ BM FLT3-WT AML cells (1 × 106 cells per mouse) were transplanted into NSG mice to generate a cohort of AML bearing PDX mice. The transplanted mice were treated with either VEH, TGN (75 mg/kg, once a day, oral gavage, 21 days), VEN (50 mg/kg, once a day, oral gavage, 21 days) or TGN/VEN at the same doses of single agents. On day 21, 106 BM MNCs cells from each treatment group were harvested for secondary transplant. (I) Left, Kaplan–Meier survival curve of primary transplanted leukemic mice treated with VEH (purple line, MS 37 days), VEN (green line, MS 41 days), TGN (blue line, MS 54 days), or TGN/VEN (red line, MS 62 days). Right, Kaplan–Meier survival curve of secondary transplanted leukemic mice treated with VEH (purple line, MS 32 days), VEN (green line, MS 39 days), TGN (blue line, MS 44 days), or TGN/VEN (red line, MS 53 days). (J-K) Synergistic effects of TGN and VEN on inv(16) PDX AML model. (J) Experimental design for TGN and VEN combined treatment. hCD45+ BM inv(16) AML cells (1 × 106 cells per mouse) were transplanted into NSGS mice to generate a cohort of AML bearing PDX mice. The transplanted mice were treated with either VEH, TGN (75 mg/kg, once a day, oral gavage, 21 days), VEN (50 mg/kg, once a day, oral gavage, 21 days) or TGN/VEN at the same doses of single agents. On day 21, 106 BM MNCs cells from each treatment group were harvested for secondary transplant. (K) Left, Kaplan–Meier survival curve of primary transplanted leukemic mice treated with VEH (purple line, MS 57 days), VEN (green line, MS 62 days), TGN (blue line, MS 80 days), or TGN/VEN (red line, MS 97 days). Right, Kaplan–Meier survival curve of secondary transplanted leukemic mice treated with VEH (purple line, MS 38 days), VEN (green line, MS 50 days), TGN (blue line, MS 61.5 days), or TGN/VEN (red line, MS 78 days). Max, maximum; OCR, oxygen consumption rate; inv(16), chromosomal inversion 16 (inv(16)(p13.1q22)).

Synergistic effects of TGN and VEN in vitro and in vivo. (A) Synergistic effect of TGN and VEN on LSC-enriched AML blasts. Primary CD34+CD38– AML blasts (1 × 105 cells per mL, n = 3) were treated with indicated concentration of TGN and VEN. Levels of cell proliferation (left) and apoptosis (right) were evaluated, and synergy score of the drug combination was calculated. Max synergy score: 48.957 (left) and 53.912 (right). (B-E) Synergistic effects of TGN and VEN on FAO/OXPHOS levels, mitochondrial fission, apoptosis, and DNA fragmentation of LSC-enriched AML blasts. Primary CD34+CD38– AML blasts (n = 4) were treated with DMSO (VEH), TGN (1 μM), VEN (20 nM), or combination of TGN and VEN for 24 hours. (B) FAO levels. (C) OXPHOS levels. (D) Mitochondria length. Left, represented TEM images. Right, quantification of mitochondria length. (E) Levels of apoptosis (left) and DNA fragmentation (right). (F-G) Synergistic effects of TGN and VEN on MllPTD/WT/Flt3ITD/ITD AML mouse model. (F) Experimental design for TGN and VEN combined treatment. Normal B6 WT recipients were IV injected with 0.5 × 106 MllPTD/WT/Flt3ITD/ITD BM MNCs. The transplanted mice were then randomly divided into 4 groups (n = 10 per group) and treated with either VEH, TGN (75 mg/kg, once a day, oral gavage, 21 days), VEN (50 mg/kg, once a day, oral gavage, 21 days) or TGN/VEN at the same doses of single agents. On day 21, 106 BM MNCs cells from each treatment group were harvested for secondary transplant. (G) Left, Kaplan–Meier survival curve of primary transplanted leukemic mice treated with VEH (purple line, MS 55 days), VEN (green line, MS 55 days), TGN (blue line, MS 67 days), or TGN/VEN (red line, MS 75 days). Right, Kaplan–Meier survival curve of secondary transplanted leukemic mice treated with VEH (purple line, MS 25 days), VEN (green line, MS 25.5 days), TGN (blue line, MS 33 days), or TGN/VEN (red line, MS 42 days). (H-I) Synergistic effects of TGN and VEN on FLT3-WT PDX AML model. (H) Experimental design for TGN and VEN combined treatment. hCD45+ BM FLT3-WT AML cells (1 × 106 cells per mouse) were transplanted into NSG mice to generate a cohort of AML bearing PDX mice. The transplanted mice were treated with either VEH, TGN (75 mg/kg, once a day, oral gavage, 21 days), VEN (50 mg/kg, once a day, oral gavage, 21 days) or TGN/VEN at the same doses of single agents. On day 21, 106 BM MNCs cells from each treatment group were harvested for secondary transplant. (I) Left, Kaplan–Meier survival curve of primary transplanted leukemic mice treated with VEH (purple line, MS 37 days), VEN (green line, MS 41 days), TGN (blue line, MS 54 days), or TGN/VEN (red line, MS 62 days). Right, Kaplan–Meier survival curve of secondary transplanted leukemic mice treated with VEH (purple line, MS 32 days), VEN (green line, MS 39 days), TGN (blue line, MS 44 days), or TGN/VEN (red line, MS 53 days). (J-K) Synergistic effects of TGN and VEN on inv(16) PDX AML model. (J) Experimental design for TGN and VEN combined treatment. hCD45+ BM inv(16) AML cells (1 × 106 cells per mouse) were transplanted into NSGS mice to generate a cohort of AML bearing PDX mice. The transplanted mice were treated with either VEH, TGN (75 mg/kg, once a day, oral gavage, 21 days), VEN (50 mg/kg, once a day, oral gavage, 21 days) or TGN/VEN at the same doses of single agents. On day 21, 106 BM MNCs cells from each treatment group were harvested for secondary transplant. (K) Left, Kaplan–Meier survival curve of primary transplanted leukemic mice treated with VEH (purple line, MS 57 days), VEN (green line, MS 62 days), TGN (blue line, MS 80 days), or TGN/VEN (red line, MS 97 days). Right, Kaplan–Meier survival curve of secondary transplanted leukemic mice treated with VEH (purple line, MS 38 days), VEN (green line, MS 50 days), TGN (blue line, MS 61.5 days), or TGN/VEN (red line, MS 78 days). Max, maximum; OCR, oxygen consumption rate; inv(16), chromosomal inversion 16 (inv(16)(p13.1q22)).

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