Dual inhibition of PI3K and Cdk9:Mcl-1 induces cell death in AML cell lines and primary human AML cells. (A) FACS-purified primary human CD34+CD38-CD123+ leukemic stem and progenitor cells were treated with 100 nM SNS-032 in the presence (+) or absence (-) of LY294002 (20 μM) and cell survival was determined at 24 hours. (B-C) Primary AML blasts were transfected with 100 nM siRNA targeting Mcl-1, Cdk9, or nontargeting siRNA control (Ctl) in the presence or absence of GDC-0941 (GDC) or A66 (1 μM) and cell survival was determined at 48 hours. (D) MV4;11 cells transduced with lentiviruses for the inducible expression of wt Bim, Bim2A, or Bim4E were treated with 1 μg/mL doxycycline and either DMSO (-) or 1 μM GDC-0941 (+) and cell survival was assessed at 48 hours. (E-F) FACS-purified primary human CD34+CD38-CD123+ leukemic stem and progenitor cells were transfected with 100 nM siRNA targeting Mcl-1 (siRNA-17 in E, siRNA-16 ,or siRNA-17 in F) or a nontargetting control siRNA (Ctl) in the presence (+) or absence (-) of either (E) LY294002 (20 μM) or (F) GDC-0941 (1 μM) and cell survival was determined at 72 hours. Results are typical of at least 2 experiments. Error bars represent standard deviations with asterisks indicating P < .05.