AMLs enriched for fatty acid metabolism and OXPHOS processes are less sensitive to cystine depletion but do depend on thioredoxin reductase activity for ROS detoxification. (A) Primary AML blasts (n = 13) were grown in liquid culture conditions, and the effects on cell proliferation upon dose-dependent depletion of cystine were determined, including EC50 values (mM) showing the effective concentration of cysteine at which a 50% reduction in proliferation was achieved. (B-C) For 10 AMLs shown in panel A, a full label-free quantitative proteome data set was available, and Pearson correlation coefficients between EC50 values and protein expression were calculated (C) and used for GSEA (B). (D) Drug screen using auranofin (0.1-0.4 μM) on a panel of primary AML samples. Relative viable cell counts at day 1 and day 4 are shown. (E) Pearson correlation coefficients were calculated between auranofin sensitivity and protein expression, and used for GSEA. (F) For 7 AMLs shown in panel D, basal oxygen consumption rates (OCR) were determined by Seahorse assay, and a correlation curve between OCR and auranofin sensitivity is shown. FDR, false discovery rate; HSC, hematopoietic stem cell; LFQ2020 UMCG, proteome label-free quantification set 2020 University Medical Centre Groningen; NES, normalized enrichment score.