Cotreatment with HHT and venetoclax or OTX015 reduces in vivo leukemia burden and significantly improves survival of mice bearing mtRUNX1 AML xenografts. (A) Total bioluminescent flux in NSG mice (n = 10) bearing OCI-AML2 RUNX1R174*/wt GFP/Luc xenografts treated for 2 weeks with OM (1 mg/kg, s.c., daily × 5 days), venetoclax (Ven) (20 mg/kg, P.O., daily × 5 days) or combination of omacetaxine with venetoclax. (B) Kaplan-Meier survival curve of NSG mice (n = 8) bearing OCI-AML2 RUNX1R174*/wt GFP/Luc xenografts treated for 3 weeks with OM, venetoclax (Ven or combination of omacetaxine with venetoclax. (C) Total bioluminescent flux in NSG mice (n = 10) bearing PDX mtRUNX1 AML#8-GFP/Luc xenografts treated for 3 weeks with OM (0.5 or 1 mg/kg s.c., daily × 5 days per week), BET inhibitor OTX015 (OTX) (30 mg/kg, P.O., daily × 5 days per week), venetoclax, (20 mg/kg, P.O., daily × 5 days per week) or combinations of 1 mg/kg omacetaxine with OTX015 or venetoclax. (D) Representative images of mice treated for 3 weeks as in panel C. (E-F) Kaplan-Meier survival curve of NSG mice (n = 8) bearing PDX mtRUNX1 AML#8-GFP/Luc xenografts treated for 6 weeks with omacetaxine OM, venetoclax, OTX015, or combinations of omacetaxine with venetoclax or omacetaxine with OTX015.