The Role of Inhibition of Apoptosis in Acute Leukemias and Myelodysplastic Syndrome

Abstract

Avoidance of apoptosis is a key mechanism that malignancies, including acute leukemias and MDS, utilize in order to proliferate and resist chemotherapy. Recently, venetoclax, an inhibitor of the anti-apoptotic protein BCL-2, has been approved for the treatment of upfront AML in an unfit, elderly population. This paper reviews the pre-clinical and clinical data for apoptosis inhibitors currently in development for the treatment of AML, ALL, and MDS.

Keywords: ALL; AML; BCL-2; MDS; intrinsic apoptosis; venetoclax.

Figure 1

Intrinsic pathway. In the resting state, suppressors BCL-2, MCL1, BCL-XL, and BCL-W bind to and inhibit effectors and activators, thus preventing downhill cascade leading to apoptosis. The site of inhibition of key BCL-2 family inhibitors is noted by brackets. In response to stress, sensitizers bind to the suppressors, releasing the inhibitory effect of suppressors on effectors and activators. Thus, conformational change and oligmerization ensues with subsequent MOMP formation and release of cycotochrome C. Cytochrome C and Apaf-1 oligmerize into the apoptosome, leading to activation of caspases and, finally, cell death.