The mitochondrial anti-apoptotic dependencies of hematologic malignancies: from disease biology to advances in precision medicine

Mitochondria are critical organelles in the regulation of intrinsic apoptosis. As a general feature of blood cancers, different anti-apoptotic members of the BCL-2 protein family localize at the outer mitochondrial membrane to sequester variable amounts of pro-apoptotic activators, and hence protect cancer cells from death induc-tion. However, the impact of distinct anti-apoptotic members on apop-tosis prevention, a concept termed anti-apoptotic dependence, differs remarkably across disease entities. Over the last two decades, several genetic and functional methodologies have been established to uncover the anti-apoptotic dependencies of the majority of blood cancers, inspiring the development of a new class of small molecules called BH3 mimetics. In this review, we highlight the rationale of targeting mito-chondrial apoptosis in hematology, and provide a comprehensive map of the anti-apoptotic dependencies that are currently guiding novel therapeutic strategies. Cell-extrinsic and -intrinsic mechanisms confer-ring resistance to BH3 mimetics are also examined, with insights on potential strategies to overcome them. Finally, we discuss how the field of mitochondrial apoptosis might be complemented with other dimen-sions of precision medicine for more successful treatment of ‘highly complex’ hematologic malignancies.