Sublethal dosing of venetoclax or MCL-1 inhibitor selects for TP53 loss clones over time. (A) In AML, ALL, or NHL cell lines in vitro or in AML xenografts, sublethal dosing of either inhibitor leads to progressive selection for the TP53 loss clone over time. (B) TP53 loss is associated with a defect in activating BAX (and BAK) in response to single-agent venetoclax or MCL-1i, but combination therapy causes high levels of activation, with cytochrome c loss leading to apoptosis. WT, wild-type; KO, knockout; MCL-1i, MCL-1 inhibitor; VEN, venetoclax; IC₂₀, 20% inhibitory concentration; IC₅₀, 50% inhibitory concentration. Panel A has been adapted from Figure 2 and panel B is a schematic based on Figure 7 in the article by Thijssen et al that begins on page 2721.