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Functionally identifiable apoptosis-insensitive subpopulations determine chemoresistance in acute myeloid leukemia
Patrick D. Bhola, … , Benjamin L. Ebert, Anthony Letai
Patrick D. Bhola, … , Benjamin L. Ebert, Anthony Letai
Published September 6, 2016
Citation Information: J Clin Invest. 2016;126(10):3827-3836. https://doi.org/10.1172/JCI82908.
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Research Article Hematology

Functionally identifiable apoptosis-insensitive subpopulations determine chemoresistance in acute myeloid leukemia

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Abstract

Upfront resistance to chemotherapy and relapse following remission are critical problems in leukemia that are generally attributed to subpopulations of chemoresistant tumor cells. There are, however, limited means for prospectively identifying these subpopulations, which hinders an understanding of therapeutic resistance. BH3 profiling is a functional single-cell analysis using synthetic BCL-2 BH3 domain–like peptides that measures mitochondrial apoptotic sensitivity or “priming.” Here, we observed that the extent of apoptotic priming is heterogeneous within multiple cancer cell lines and is not the result of experimental noise. Apoptotic priming was also heterogeneous in treatment-naive primary human acute myeloid leukemia (AML) myeloblasts, and this heterogeneity decreased in chemotherapy-treated AML patients. The priming of the most apoptosis-resistant tumor cells, rather than the median priming of the population, best predicted patient response to induction chemotherapy. For several patients, these poorly primed subpopulations of AML tumor cells were enriched for antiapoptotic proteins. Developing techniques to identify and understand these apoptosis-insensitive subpopulations of tumor cells may yield insights into clinical chemoresistance and potentially improve therapeutic outcomes in AML.

Authors

Patrick D. Bhola, Brenton G. Mar, R. Coleman Lindsley, Jeremy A. Ryan, Leah J. Hogdal, Thanh Trang Vo, Daniel J. DeAngelo, Ilene Galinsky, Benjamin L. Ebert, Anthony Letai

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Figure 5

Poorly primed subpopulations predict complete remission in AML.

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Poorly primed subpopulations predict complete remission in AML.
(A) Dose...
(A) Dose-response curve of cytochrome c loss in BIM cells is used to identify the different effective concentrations of the BIM peptide. (B) Correlation of BIM EC50 and remission status of patients (P = 0.28, Mann-Whitney U test). (C) Correlation of BIM EC90 and remission status of patients (P = 0.002, Mann-Whitney U test). Error bars represent SD. (D and E) ROC for the BIM EC50 and BIM EC90 in predicting complete remission. (F) Area under curve from ROC analysis for different effective concentration cutoffs of the BIM peptide. The curve peaks at an effective concentration of 95%.

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