Differential mitochondrial priming of AML cells modulates clinical responses to therapy.
Major finding: Differential mitochondrial priming of AML cells modulates clinical responses to therapy.
Clinical relevance: AML myeloblasts are more sensitive to BCL-2 inhibition than normal HSCs.
Impact: BH3 profiling may be a prognostic and predictive biomarker of response to therapy in AML.
Cytotoxic chemotherapy successfully cures a large percentage of patients with acute myelogenous leukemia (AML), but some patients do not respond to these agents or experience tumor relapse and must undergo allogeneic stem cell transplantation. Therefore, identifying patients at high risk for relapse is crucial to the selection of therapeutic strategies. Vo and colleagues hypothesized that the readiness of AML cells for apoptosis, defined as mitochondrial priming, underlies the variability in clinical responses to chemotherapy, and they used BH3 profiling to measure mitochondrial apoptotic function in response to proapoptotic BH3 domain peptides. In support of this hypothesis, mitochondrial priming of AML cell lines mediated increased chemosensitivity to topoisomerase II inhibitors, and higher pretreatment apoptotic priming of patient-derived AML myeloblasts was correlated with complete and long-term response to chemotherapy. BH3 profiling identified patients likely to achieve complete remission and those with low apoptotic priming at high risk of relapse who would benefit from allogeneic transplantation. Furthermore, mitochondrial priming was decreased in AML cells after relapse as compared with pretreatment levels, suggestive of in vivo selection for cells further from the apoptotic threshold. Intriguingly, patients whose myeloblasts were more primed than normal hematopoietic stem cells (HSC) were more responsive to treatment and survived longer than patients whose myeloblasts were less primed than HSCs, indicating that differential priming between these cells defines the therapeutic index of chemotherapy. Strikingly, both chemosensitive and chemoresistant AML cells were uniquely dependent on BCL2 and thus more sensitive to treatment with a BCL-2 inhibitor compared with normal HSCs, suggesting that BCL-2–targeted therapy may be clinically effective, particularly against refractory AML. These results suggest that BH3 profiling is a predictive biomarker of therapeutic responses in AML and may help to guide development of personalized therapies for this disease.