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

Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors

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 7

AML cells have increased lysosomal mass compared with normal hematopoietic cells.

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AML cells have increased lysosomal mass compared with normal hematopoiet...
(A) Lysosome size (nm2) and number were quantified by TEM in AML cells and primary AML and normal samples. Data represent mean ± SEM (left panel) (*P < 0.05; **P < 0.01; ***P < 0.001). The arrow indicates a CD34+ AML sample. (B) Ordered heat maps illustrating expression of lysosome biogenesis genes in functionally defined bulk AML cells (CD34+ cells from 6 samples, CD34–CD38+ cells from 12 samples, and CD34–CD38– cells from 11 samples) versus normal CD34+ cord blood–derived HSCs (n = 3 samples). Data are derived from the dataset GSE30377, archived in the GEO database. Genes are rank ordered by fold change and significance. (C) Ordered heat maps illustrating expression of a subset of lysosome biogenesis genes in functionally defined LIC-enriched cell populations (CD34+CD38– cells from 13 samples and CD34+CD38+ cells from 6 samples, as indicated) versus HSCs (n = 3 samples). Up and Down indicated upregulated and downregulated, respectively. (D) Expression of lysosomal cathepsins in functionally defined bulk AML cells (as in B) versus normal CD34+ cord blood–derived HSCs (n = 3 samples). (E) Expression of lysosomal cathepsins in functionally defined LIC-enriched cell populations (as in C) versus HSCs (n = 3 samples).