Summary of key preclinical and clinical characteristics of hematologic cancers where BCL2 inhibitors demonstrate clinical activity. At the single cell level, high vulnerability to BCL2 inhibition (left) is typically observed when BCL2 expression is constitutively high, and there is relatively minor expression of other prosurvival proteins.^17,133 These BCL2-dependent cells reflect the near totality of cells among populations where CRs can readily be induced with monotherapy (eg, CLL,^{11,17,27,30,31,41} some MCL,^103,105 t(11;14) myeloma and myeloma with heightened BCL2:BCLxl expression,^96,97,123IDH-mutant AML^69,80). For these cell populations, BH3 mimetics like venetoclax strike the bullseye. More commonly (right), cells are not BCL2 dependent, and BCL2 is not the bullseye. Rather these cells are vulnerable to BCL2 inhibition when a wave (depicted as green lines) of secondary inhibition of other prosurvival proteins by displaced BH3-only proteins¹³⁴ is initiated, resulting in antagonism of other prosurvival proteins and BCL2. In these partially BCL2-dependent cells, BCL2 inhibitor monotherapy may be insufficient to kill cells with these characteristics (moderate and variable BCL2 expression, relatively higher levels of MCL1 or BCLxL), but some cells will die, whereas others suffer sublethal injury consequent on BAX/BAK-dependent mitochondrial depolarization and reduced energy production.^53,91 Additional stressors will be required to maximize apoptosis and achieve high response rates in diseases in which the majority of cells are affected in this manner. This includes most myeloma,⁹⁷ AML,^67,69,135 ALL,¹⁶ and many B-cell lymphomas.^17,105,136 Adapted¹³⁷ with permission. Professional illustration by Somersault18:24.