期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 123, 期 1, 页码 315-328出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI64180
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资金
- Leukemia and Lymphoma Society
- International Myeloma Foundation
- Canadian Stem Cell Network
- Ontario Institute of Cancer Research
- Ontario Ministry of Research and Innovation
- Ministry of Health and Long-Term Care in the Province of Ontario
- Canadian Institutes of Health Research (CIHR)
- Terry Fox Foundation
- National Human Genome Research Institute (NHGRI)
- Canadian Cancer Society [020380]
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 lysosotnal disruption preferentially targets AML cells and AML progenitor cells, providing a rationale for testing lysosomal disruption as a novel therapeutic strategy for AML.
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