Fig. 5: ABCC1 inhibition reverses Venetoclax-resistance in AML cells.

A Dose–response curves of Venetoclax in MOLM-13, HL-60 and THP-1 cells after 5 days of treatment. Data are presented as mean values ± SD. n = 3 experimental replicates. B Competitive proliferation assay of THP-1-Cas9 cells treated with 500 nM Venetoclax for 38 days. Percentages of sgRNA/IRFP670+ cells were normalized to day 0 of treatment and to DMSO controls. Data are presented as mean values ± SD. n = 3 experimental replicates. The corresponding flow cytometric gating strategy for IRFP670+ cells is depicted in Supplementary Fig. 6A. C Growth curves of THP-1 cells treated with DMSO, 1 µM Venetoclax, 2 µM Reversan or 1 µM Venetoclax in combination with 2 µM Reversan. Data are presented as mean values ± SD. n = 3 experimental replicates. D Ion count ratio of intracellular Venetoclax to Threonine (control amino acid) as determined by LC-MS/MS of Cas9-expressing THP-1 cells transduced with either sgAAVS1.1 or sgABCC1.1. Data are presented as mean values ± SD. n = 2 experimental replicates. Significance was determined with an unpaired Student’s t test with two-tailed P value as indicated. E Schematic representation of the generation of Venetoclax-resistant MOLM-13 and MV4-11 cells. Cells were treated up to 2.5 months using increasing concentrations of Venetoclax, until they showed stable growth in media supplemented with 1 μM Venetoclax. F Dose–response curves of Venetoclax in MV4-11 wild-type and Venetoclax-resistant cells co-treated with either DMSO or 5 µM Reversan for 5 days. Data are presented as mean values ± SD. n = 3 experimental replicates. G Growth curves of Venetoclax-resistant MV4-11 treated with DMSO, 1 µM Venetoclax, 2 µM Reversan or 1 µM Venetoclax in combination with 2 µM Reversan. Data are presented as mean values ± SD. n = 3 experimental replicates. A–D, F, G Source data are provided as a Source Data file.