Targeting Bcl-2 Proteins in Acute Myeloid Leukemia

Abstract

B cell lymphoma 2 (BCL-2) family proteins play an important role in intrinsic apoptosis. Overexpression of BCL-2 proteins in acute myeloid leukemia can circumvent resistance to apoptosis and chemotherapy. Considering this effect, the exploration of anti-apoptotic BCL-2 inhibitors is considered to have tremendous potential for the discovery of novel pharmacological modulators in cancer. This review outlines the impact of BCL-2 family proteins on intrinsic apoptosis and the development of acute myeloid leukemia (AML). Furthermore, we will also review the new combination therapy with venetoclax that overcomes resistance to venetoclax and discuss biomarkers of treatment response identified in early-phase clinical trials.

Keywords: AML—acute myeloid leukemia; B cell lymphoma 2; Bcl-2 protein; intrinsic apoptosis; venetoclax (ABT-199).

Figure 1

The extrinsic and intrinsic pathways to apoptosis. The extrinsic pathway of apoptosis is activated when certain death receptor ligands of the tumour necrosis factor (TNF) family (such as TNF) engage their cognate death receptors on the plasma membrane, leading to caspase-8 activation via the death-inducing signalling complex (DISC), which results in apoptosis. The intrinsic pathway of apoptosis is activated by cellular stresses (such as DNA damage, growth factor deprivation or oxidative stress) and is regulated by BCL-2 family proteins. BH3 proteins bind to and activate pro-apoptotic proteins BAX, BAK and possibly BOK, which oligomerize in the mitochondrial membranes and release cytochrome c, then interact with apoptosis protease-activating factor 1(APAF1) and initiate caspase activation that results in apoptosis. Futhermore, BH3-only activator proteins (BID, BIM, Puma and NOXA) directly bind to interact with BAX and BAK to promote mitochondrial outer membrane permeabilization (MOMP). While the BH3-only sensitizer proteins (BAD, BIK, HRK, BMF, PUMA, NOXA) bind to anti-apoptotic proteins with higher affinity, freeing the activator proteins from the BH3 binding pockets in the anti-apoptotic proteins and executing cell death by binding to BAX or BAK. The two pathways converge at activation of the effector caspase-3.

Figure 2

The selectivity of BCL-2 family proteins. (A) BAK is inhibited predominantly by BCL-XL, MCL-1 and BFL-1, while BCL-2 contributes in some situations. However, BAX is probably inhibited by all of the pro-survival proteins. (B) Some BH3-only proteins, such as BAD and NOXA, are selective for subsets of their anti-apoptotic relatives, whereas other BH3-only proteins, particularly BIM, BID and PUMA, probably neutralize all of the anti-apoptotic proteins.