Direct and indirect alterations to apoptosis regulators explain many of the proven mechanisms of clinical resistance to venetoclax. The graphic highlights the interrelations between validated genetic and epigenetic mechanisms of venetoclax resistance observed in patients (tier 1 mechanisms listed in Table 3 with references) and their convergence on the expression or function of BCL2 family proteins and/or on mitochondria. Genetic aberrations in BCL2 family members such as amplifications affecting MCL1, coding mutations in BCL2 (*such as encode BCL2 Gly101Val) that alter venetoclax binding, or nonsense mutations (eg, BAX) may occur. Alternatively, genetic changes in their regulators (eg, TP53, del9p, members of the SWI/SNF complex) may alter their expression indirectly (epigenetic changes [Δ]). TP53 loss or mutation (in green) can indirectly reduce sensitivity to venetoclax by reducing expression of BH3-only proteins (eg, PUMA, NOXA) and/or by increasing the threshold for BAX/BAK-induced permeabilization of the outer mitochondrial membrane.⁸³ Activated signaling in various growth factor pathways (in blue; eg, via kinase mutations) can indirectly increase expression of other prosurvival proteins or increase mitochondrial metabolism.