title: 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.affiliation: Princess Margaret Hospital/the Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Mahadeo A
authors.initials: MA
authors.lastname: Sukhai
authors.forename: Swayam
authors.initials: S
authors.lastname: Prabha
authors.forename: Rose
authors.initials: R
authors.lastname: Hurren
authors.forename: Angela C
authors.initials: AC
authors.lastname: Rutledge
authors.forename: Anna Y
authors.initials: AY
authors.lastname: Lee
authors.forename: Shrivani
authors.initials: S
authors.lastname: Sriskanthadevan
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wang
authors.forename: Marko
authors.initials: M
authors.lastname: Skrtic
authors.forename: Ayesh
authors.initials: A
authors.lastname: Seneviratne
authors.forename: Maria
authors.initials: M
authors.lastname: Cusimano
authors.forename: Bozhena
authors.initials: B
authors.lastname: Jhas
authors.forename: Marcela
authors.initials: M
authors.lastname: Gronda
authors.forename: Neil
authors.initials: N
authors.lastname: MacLean
authors.forename: Eunice E
authors.initials: EE
authors.lastname: Cho
authors.forename: Paul A
authors.initials: PA
authors.lastname: Spagnuolo
authors.forename: Sumaiya
authors.initials: S
authors.lastname: Sharmeen
authors.forename: Marinella
authors.initials: M
authors.lastname: Gebbia
authors.forename: Malene
authors.initials: M
authors.lastname: Urbanus
authors.forename: Kolja
authors.initials: K
authors.lastname: Eppert
authors.forename: Dilan
authors.initials: D
authors.lastname: Dissanayake
authors.forename: Alexia
authors.initials: A
authors.lastname: Jonet
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dassonville-Klimpt
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Li
authors.forename: Alessandro
authors.initials: A
authors.lastname: Datti
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
authors.forename: Jeff
authors.initials: J
authors.lastname: Wrana
authors.forename: Ian
authors.initials: I
authors.lastname: Rogers
authors.forename: Pascal
authors.initials: P
authors.lastname: Sonnet
authors.forename: William Y
authors.initials: WY
authors.lastname: Ellis
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Corey
authors.forename: Connie
authors.initials: C
authors.lastname: Eaves
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.forename: Jean C Y
authors.initials: JC
authors.lastname: Wang
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
authors.forename: Corey
authors.initials: C
authors.lastname: Nislow
authors.forename: Guri
authors.initials: G
authors.lastname: Giaever
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D055785:Gene Knockdown Techniques; D055106:Genome-Wide Association Study; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism* / Q000473:pathology; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008297:Male; D015767:Mefloquine / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D010539:Permeability / Q000187:drug effects; D012441:Saccharomyces cerevisiae / Q000235:genetics; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D000962:Antimalarials; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins; D015767:Mefloquine; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C497811:LAMP2 protein, human; C052255:Lamp1 protein, mouse