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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.

SUBMITTER: Sukhai MA

PROVIDER: S-EPMC3533286 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors.

Sukhai Mahadeo A MA Prabha Swayam S Hurren Rose R Rutledge Angela C AC Lee Anna Y AY Sriskanthadevan Shrivani S Sun Hong H Wang Xiaoming X Skrtic Marko M Seneviratne Ayesh A Cusimano Maria M Jhas Bozhena B Gronda Marcela M MacLean Neil N Cho Eunice E EE Spagnuolo Paul A PA Sharmeen Sumaiya S Gebbia Marinella M Urbanus Malene M Eppert Kolja K Dissanayake Dilan D Jonet Alexia A Dassonville-Klimpt Alexandra A Li Xiaoming X Datti Alessandro A Ohashi Pamela S PS Wrana Jeff J Rogers Ian I Sonnet Pascal P Ellis William Y WY Corey Seth J SJ Eaves Connie C Minden Mark D MD Wang Jean C Y JC Dick John E JE Nislow Corey C Giaever Guri G Schimmer Aaron D AD

The Journal of clinical investigation 20121203 1

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 ident ...[more]

PMID: 23202731

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Project description:Spleen tyrosine kinase (SYK) is an important oncogene and signaling mediator activated by cell surface receptors crucial for acute myeloid leukemia (AML) maintenance and progression. Genetic or pharmacologic inhibition of SYK in AML cells leads to increased differentiation, reduced proliferation, and cellular apoptosis. Herein, we addressed the consequences of SYK inhibition to leukemia stem-cell (LSC) function and assessed SYK-associated pathways in AML cell biology. Using gain-of-function MEK kinase mutant and constitutively active STAT5A, we demonstrate that R406, the active metabolite of a small-molecule SYK inhibitor fostamatinib, induces differentiation and blocks clonogenic potential of AML cells through the MEK/ERK1/2 pathway and STAT5A transcription factor, respectively. Pharmacological inhibition of SYK with R406 reduced LSC compartment defined as CD34+CD38-CD123+ and CD34+CD38-CD25+ in vitro, and decreased viability of LSCs identified by a low abundance of reactive oxygen species. Primary leukemic blasts treated ex vivo with R406 exhibited lower engraftment potential when xenotransplanted to immunodeficient NSG/J mice. Mechanistically, these effects are mediated by disturbed mitochondrial biogenesis and suppression of oxidative metabolism (OXPHOS) in LSCs. These mechanisms appear to be partially dependent on inhibition of STAT5 and its target gene MYC, a well-defined inducer of mitochondrial biogenesis. In addition, inhibition of SYK increases the sensitivity of LSCs to cytarabine (AraC), a standard of AML induction therapy. Taken together, our findings indicate that SYK fosters OXPHOS and participates in metabolic reprogramming of AML LSCs in a mechanism that at least partially involves STAT5, and that SYK inhibition targets LSCs in AML. Since active SYK is expressed in a majority of AML patients and confers inferior prognosis, the combination of SYK inhibitors with standard chemotherapeutics such as AraC constitutes a new therapeutic modality that should be evaluated in future clinical trials.

Dataset Information

Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors.

Publications

Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors.

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