Despite decades of successful use of cytotoxic chemotherapy in acute myelogenous leukemia (AML), the biological basis for its differential success among individuals and for the existence of a therapeutic index has remained obscure. Rather than taking a genetic approach favored by many, we took a functional approach to ask how differential mitochondrial readiness for apoptosis (“priming”) might explain individual variation in clinical behavior. We found that mitochondrial priming measured by BH3 profiling was a determinant of initial response to induction chemotherapy, relapse after remission, and requirement for allogeneic bone marrow transplantation. Differential priming between malignant myeloblasts and normal hematopoietic stem cells supports a mitochondrial basis to the therapeutic index for chemotherapy. BH3 profiling identified BCL-2 inhibition as a targeted strategy likely to have a useful therapeutic index. BH3 profiling refines predictive information provided by conventional biomarkers currently in use and thus may itself have utility as a clinical predictive biomarker.
► Mitochondrial priming of AML versus HSCs determines the chemotherapeutic index ► Pretreatment BH3 profiling may have utility as a clinical decision-making tool ► Myeloblasts tend to be BCL-2 dependent, but human HSCs tend to be MCL-1 dependent ► Targeting BCL-2 is selectively toxic to even chemorefractory myeloblasts over HSCs
