Strategies targeting apoptosis proteins to improve therapy of chronic lymphocytic leukemia

A typical feature of chronic lymphocytic leukemia (CLL) is the impaired ability of the leukemic cells to execute their apoptotic suicide program. Various strategies have been developed to restore apoptosis in CLL cells ex vivo. This article reviews the strategies targeting proteins that directly regulate the mitochondrial pathway of apoptosis and caspase activation: (i) inhibiting the expression or activity of prosurvival proteins of the Bcl-2 and IAP (inhibitor of apoptosis protein) families, which are overexpressed in CLL cells and (ii) upregulating proapoptotic BH3-only members of the Bcl-2 family (which are antagonists of the prosurvival members). Preclinical and clinical data have revealed that inhibiting the activity of prosurvival Bcl-2 proteins with BH3 mimetics (so-called because they mimic BH3-only proteins) is an attractive strategy for CLL therapy. Recent results suggest that the development of BH3 mimetics capable of directly activating the apoptosis effectors Bax and Bak may also be envisaged.