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Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors
Mahadeo A. Sukhai, … , Guri Giaever, Aaron D. Schimmer
Mahadeo A. Sukhai, … , Guri Giaever, Aaron D. Schimmer
Published December 3, 2012
Citation Information: J Clin Invest. 2013;123(1):315-328. https://doi.org/10.1172/JCI64180.
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Research Article Oncology Article has an altmetric score of 26

Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors

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Abstract

Despite efforts to understand and treat acute myeloid leukemia (AML), there remains a need for more comprehensive therapies to prevent AML-associated relapses. To identify new therapeutic strategies for AML, we screened a library of on- and off-patent drugs and identified the antimalarial agent mefloquine as a compound that selectively kills AML cells and AML stem cells in a panel of leukemia cell lines and in mice. Using a yeast genome-wide functional screen for mefloquine sensitizers, we identified genes associated with the yeast vacuole, the homolog of the mammalian lysosome. Consistent with this, we determined that mefloquine disrupts lysosomes, directly permeabilizes the lysosome membrane, and releases cathepsins into the cytosol. Knockdown of the lysosomal membrane proteins LAMP1 and LAMP2 resulted in decreased cell viability, as did treatment of AML cells with known lysosome disrupters. Highlighting a potential therapeutic rationale for this strategy, leukemic cells had significantly larger lysosomes compared with normal cells, and leukemia-initiating cells overexpressed lysosomal biogenesis genes. These results demonstrate that lysosomal disruption preferentially targets AML cells and AML progenitor cells, providing a rationale for testing lysosomal disruption as a novel therapeutic strategy for AML.

Authors

Mahadeo A. Sukhai, Swayam Prabha, Rose Hurren, Angela C. Rutledge, Anna Y. Lee, Shrivani Sriskanthadevan, Hong Sun, Xiaoming Wang, Marko Skrtic, Ayesh Seneviratne, Maria Cusimano, Bozhena Jhas, Marcela Gronda, Neil MacLean, Eunice E. Cho, Paul A. Spagnuolo, Sumaiya Sharmeen, Marinella Gebbia, Malene Urbanus, Kolja Eppert, Dilan Dissanayake, Alexia Jonet, Alexandra Dassonville-Klimpt, Xiaoming Li, Alessandro Datti, Pamela S. Ohashi, Jeff Wrana, Ian Rogers, Pascal Sonnet, William Y. Ellis, Seth J. Corey, Connie Eaves, Mark D. Minden, Jean C.Y. Wang, John E. Dick, Corey Nislow, Guri Giaever, Aaron D. Schimmer

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Figure 5

Characterization of mefloquine diastereomers’ effects on cell viability and lysosome integrity.

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Characterization of mefloquine diastereomers’ effects on cell viability ...
(A) Chemical structures of mefloquine diastereomers. (B) OCI-AML2 cells were treated with increasing concentrations of the indicated mefloquine diastereomer for 48 hours. After incubation, cell viability was measured by MTS. Relative viability was calculated in comparison to the vehicle-treated controls. Data represent the mean percent viability ± SD from 3 replicates in a representative experiment. (C) OCI-AML2 cells were treated with increasing concentrations of the indicated mefloquine diastereomer for 24 hours. After incubation, lysosome integrity was measured by LysoTracker staining and flow cytometry. Relative lysosome integrity was calculated in comparison to the vehicle-treated control cells. Data represent the mean percent lysosome integrity ± SD from 3 replicates in a representative experiment.

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

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