A. Cytarabine (orange) and anthracyclines such as daunorubicin (red) and idarubicin work in concert to prevent DNA synthesis in rapidly dividing cells, including leukemic blasts, thereby leading to cell death. However, chemoresistant subclones (red, orange, green circles) may persist, particularly quiescent leukemic stem cells (LSCs; shown with red circular arrows). B. Azacitidine (green) has long been used as a monotherapy to alter leukemic cell gene expression by incorporating into both DNA and RNA, inhibiting methyltransferases, and reducing nucleic acid methylation. Venetoclax (light blue) inhibits the anti-apoptotic protein BCL-2, which resides in the outer mitochondrial membrane. Combined, they appear to disproportionately disrupt LSC metabolism due to dependence on oxidative phosphorylation, potentially targeting the LSCs more effectively. TOP2, topoisomerase 2; DNMT, DNA methyltransferase.