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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 2

Mefloquine synergizes with ROS-producing compounds that target the lysosome.

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Mefloquine synergizes with ROS-producing compounds that target the lysos...
(A) TEX (left panel) and OCI-AML2 (right panel) cells were treated with mefloquine (5 and 10 μM) or vehicle control for 24 hours and ROS levels measured using 5-(and-6)-carboxy-2′7′-dichlorodihydrofluorescein diacetate (carboxy-H2DCFDA) staining. Data represent the mean ± SD fold increase in ROS compared with vehicle control–treated cells from 3 replicates in a representative experiment. (B) Four primary AML samples (left panel: samples 1–3 sensitive to mefloquine; sample 4 insensitive to mefloquine; see Supplemental Figure 2B) and 2 normal PBSC samples (right panel) were treated with mefloquine for 24 hours and ROS levels measured using carboxy-H2DCFDA staining and flow cytometry (*P < 0.05). (C) Heat maps demonstrating the induction of ROS, measured as in A, in TEX leukemia cells treated with combinations of mefloquine and artesunate or artenimol, as indicated. EOBA score is as defined in Supplemental Methods. (D) TEX cells were treated with mefloquine (8 μM) for 48 hours alone or in combination with the ROS scavengers α-tocopherol (3 mM) and NAC (10 mM). After incubation, cell viability was measured by Annexin V/PI staining. Data represent the mean ± SD fold increase in ROS production compared with vehicle control–treated cells from 3 replicates in a representative experiment (there was significant protection against mefloquine-mediated cell death after scavenger treatment: P < 0.05).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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