Potency and specificity of BH3 mimetic compounds in myeloma cell lines or primary myeloma samples. (A) BAX/BAK-dependent killing of KMS-12-PE myeloma cells by an inhibitor of BCL2. The viability of WT KMS-12-PE cells or ones engineered to lack BAX and BAK 48 hours after treatment with 0 to 10 μM of the BCL2-selective inhibitor ABT-199 was determined using the CellTiter-Glo assay. (B) Similar results to A, but obtained from treating WT or BAX^−/−BAK^−/− MM1S myeloma cells with the BCLXL inhibitor A5463. (C) Sensitivity of primary myeloma samples to the BH3 mimetics. The viability of 12 primary myeloma samples were determined 72 h after treatment with 1 μM ABT-199, ABT-737, or the BCLXL inhibitor A1852 ex vivo; the samples were ranked according to their sensitivity to each drug. (D) Sensitivity of a MCL1-dependent cell line OPM-2³⁰  to putative inhibitors of MCL1. The viability of WT OPM-2 or a BAX^−/−BAK^−/−-deficient clone 48 hours after treatment with 0 to 10 μM of obatoclax (in black) or the MCL1-selective inhibitor A-1210477 (in blue) was determined using the CellTiter-Glo assay. (E) Sensitivity of another MCL1-dependent cell line H929^33,35  to putative inhibitors of MCL1. Similar experiments to that described in panel D, but undertaken with H929 cells instead. The dotted horizontal line represents 50% loss in viability. The results in panels A, B, D, and E represent the mean values from 3 independent experiments; data are shown as means ± 1 SD.