Relative Mitochondrial Priming of Myeloblasts and Normal HSCs Determines Chemotherapeutic Success in AML

SummaryDespite 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.PaperClip To listen to this audio, enable JavaScript on your browser. However, you can download and play the audio by clicking on the icon belowHelp with MP3 filesOptionsDownload audio (3805 K)

Graphical AbstractFigure optionsDownload high-quality image (333 K)Download as PowerPoint slideHighlights
► 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