Relative Mitochondrial Priming of Myeloblasts and Normal HSCs Determines Chemotherapeutic Success in AML
Menée sur des lignées cellulaires de leucémie aiguë myéloblastique et des échantillons tumoraux, cette étude met en évidence un mécanisme, lié à l'apoptose dans les mitochondries, et un biomarqueur associé, BH3, susceptible de prédire la réponse à une chimiothérapie cytotoxique
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.
º Mitochondrial priming of AML versus HSCs determines the chemotherapeutic index
º Pretreatment BH3 profiling may have utility as a clinical decision-making tool
º Myeloblasts tend to be BCL-2 dependent, but human HSCs tend to be MCL-1 dependent
º Targeting BCL-2 is selectively toxic to even chemorefractory myeloblasts over HSCs If the HSCs are more primed for apoptosis than the leukemia, then the patient will be severely affected by chemotherapy without curing the cancer, whereas in the opposite scenario, the leukemia is targeted effectively while the patient recovers well.
Cell , article en libre accès, 2011