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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