Regulation of the intrinsic (mitochondrial) pathway to apoptosis by the BCL2 protein family and mechanism of action of BH3 mimetics in normal cells and selected hematologic neoplasms. (A) In most normal cells, multiple prosurvival BCL2 proteins act to maintain their survival by preventing the activation of the cell death effectors BAX and BAK. Cellular stresses upregulate the BH3-only proteins (eg, BIM, BAD, PUMA, NOXA) that act by binding to BCL2 or its prosurvival relatives (MCL1, BCLxL, BCLw, BCL2A1). These interactions between BH3-only proteins and prosurvival proteins can be specific (eg, BAD only binds BCL2, BCLxL, and BCLW with high affinity; NOXA only binds MCL1 and BCL2A1) or more encompassing (eg, BIM and PUMA will bind all prosurvival proteins with high affinity).¹²¹ Tight binding of the BH3-only proteins blocks the ability of the prosurvival BCL2 proteins to hold BAX/BAK in check. The threshold for apoptosis is determined largely by the relative abundance of the key players and this varies according to cell lineage and microenvironmental cues. In many hematologic cancers, oncogenic stress-induced BH3-only protein activity means that the threshold for inducing apoptosis is low with the malignant cell being “primed for death” in some instances.² (B) BCL2 expression is often dysregulated in CLL with high levels of expression and the leukemic cells are heavily reliant on BCL2.^17,30,122 Hence, CLL cells are susceptible to the selective inhibition of BCL2 with venetoclax (in red). Inhibition of BCL2 by venetoclax allows activated BAX/BAK oligomers to form on the mitochondrial outer membrane, permeabilizing it and thereby compromising normal mitochondrial function (eg, reduced ATP production), as well as triggering the leakage of intramitochondrial molecules (eg, cytochrome c; green). These trigger the activation of proteolytic caspases that lead to cellular demolition. Because BAX/BAK are essential to drive MOMP, they are required for the action of venetoclax and all true BH3 mimetics. (C) In normal plasma cells and in many cases of multiple myeloma, especially relapsed disease, the predominant survival protein expressed is MCL1.^7,117,123 Hence, MCL1 inhibition (in green) could well prove to be effective for this plasma cell malignancy. However, as indicated by the red asterisk, some subtypes of multiple myeloma are also highly susceptible to BCL2 inhibition (see Figure 2). (D) In AML, the degree of dependence on BCL2 or on MCL1 varies, with some subtypes being more BCL2 reliant than others (see Figure 2). Overall, both BCL2 and MCL1 appear to play prominent prosurvival roles in most AML cases. Loss of oxidative phosphorylation and energy production after MOMP is a prominent effect of venetoclax in AML cells.^91,124 Professional illustration by Somersault18:24.