High-throughput screening identifies BCL-XL inhibitors with selective efficacy against erythroid and megakaryoblastic leukemias. (A) Schematic of the high-throughput drug sensitivity and resistance testing experiments. Four erythroid (F36P, HEL, OCIM1, and TF1), 2 megakaryoblastic (CMK and M07), and 3 other AML cell lines (MOLM13, MV411, and OCIAML2) were screened using over 500 drugs in 5 different concentrations. In addition, a focused screen using 8 BCL-2 family inhibitors in 9 different concentrations in 4 erythroid, 2 megakaryoblastic, and 15 other AML cell lines was performed. (B) Volcano plot of drug sensitivity of erythroid or megakaryoblastic AML cell lines (n = 6) compared with other AML (n = 3) from screening of 528 compounds. Drugs with FDR <5% are colored in dark gray and drugs with FDR <5% and absolute differential DSS >15 are colored in red or blue. In addition, S-63845 targeting MCL-1 is colored in blue. (C) Dose-response curves of the BCL-XL inhibitor A-1331852, the BCL-2 inhibitor venetoclax, and the BCL-2/BCL-XL inhibitor navitoclax in 21 AML cell lines. DSS, drug sensitivity score; FDR, false discovery rate.