Mechanism of action of venetoclax (ABT-199) in myeloid malignant cells. In blast cells, venetoclax inhibits BCL-2 protein, thereby reducing the inhibitory effect of BCL-2 on the proapoptotic complex. Venetoclax also inhibits oxidative phosphorylation (OXPHOS) in the mitochondria. Upregulation of MCL-1 or BCL-XL, metabolic reprogramming, or BCL-2/BAX mutations can occur in blast cells as a compensatory effect and escape mechanism (red text and arrows). Normal cells, which rely on MCL-1 signaling, are less sensitive to venetoclax inhibition. BAX, BCL-2–associated X protein.