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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 Article has an altmetric score of 39

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 6

Differential immunofluorescence of BCL-2 proteins in unprimed cells.

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Differential immunofluorescence of BCL-2 proteins in unprimed cells.
(A)...
(A) Imunofluorescent staining of BCL-2 in cells after BH3 profiling of AML72 indicates that BCL-2 expression is low in primed cells and relatively higher in unprimed cells. (B) No difference in MnSOD staining in primed or unprimed cells. (C) Quantification of protein expression in the 10% most primed cells (primed), in the 10% least primed cells (unprimed), and in all cells (all). Error bars represent 95% CI of individual cells. (D) Quantification of the ratio of protein expression in unprimed/primed cells in different primary AML tumors for several apoptotic proteins. Red indicates that the protein is preferentially expressed in unprimed fractions. (E) Different populations of AML567 that were sorted and separately sequenced.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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