Aldehyde dehydrogenases inhibition eradicates leukemia stem cells while sparing normal progenitors.
The vast majority of patients with acute myeloid leukemia (AML) achieve complete remission (CR) after standard induction chemotherapy. However, the majority subsequently relapse and die of the disease. A leukemia stem cell (LSC) paradigm has been invoked to explain this failure of CR to reliably translate into cure. Indeed, LSCs are highly enriched in CD34+CD38- leukemic cells that exhibit positive aldehyde dehydrogenase activity (ALDH+) on flow cytometry, these LSCs are resistant to currently existing treatments in AML such as cytarabine and anthracycline that, at the cost of great toxicity on normal cells, are highly active against the leukemic bulk, but spare the LSCs responsible for relapse. To try to combat the LSC population selectively, a well-characterized ALDH inhibitor by the trivial name of dimethyl ampal thiolester (DIMATE) was assessed on sorted CD34+CD38- subpopulations from AML patients and healthy patients. ALDH activity and cell viability were monitored by flow cytometry. From enzyme kinetic studies DIMATE is an active enzyme-dependent, competitive, irreversible inhibitor of ALDH1. On cells in culture, DIMATE is a powerful inhibitor of ALDHs 1 and 3, has a major cytotoxic activity on human AML cell lines. Moreover, DIMATE is highly active against leukemic populations enriched in LSCs, but, unlike conventional chemotherapy, DIMATE is not toxic for healthy hematopoietic stem cells which retained, after treatment, their self-renewing and multi-lineage differentiation capacity in immunodeficient mice, xenografted with human leukemic cells. DIMATE eradicates specifically human AML cells and spares healthy mouse hematologic cells.
Aix-Marseille Université, INSERM, UMR1090, TAGC Campus, Marseille, France.|Department of Hematology and Cellular therapy, AP-HM, Conception Hospital, Marseille, France.|Advanced BioDesign, Lyon, France.
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Venton
Lab Animal Models and Cancer Laboratory Anatomy Pathology Program, Institut de Recerca Valld' Hebron, Barcelona, Spain.
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Pérez-Alea
Aix-Marseille Université, INSERM, UMR1090, TAGC Campus, Marseille, France.|Advanced BioDesign, Lyon, France.
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Baier
Univ Lyon, Université Claude Bernard Lyon 1, ICBMS UMR5246, Villeurbanne, France.
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Fournet
Advanced BioDesign, Lyon, France.
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Quash
Aix-Marseille Université, INSERM, UMR1090, TAGC Campus, Marseille, France.
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Labiad
Advanced BioDesign, Lyon, France.
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Martin
Department of Apheresis and Autotransfusion, APHM, Conception Hospital, Marseille, France.
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Sanderson
Department of Apheresis and Autotransfusion, APHM, Conception Hospital, Marseille, France.
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Poullin
Hematology laboratory, APHM, Hôpital de la Timone, Marseille, France.|UMR 1062 NORT, INSERM, Marseille, France.
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Suchon
Department of Hematology and Cellular therapy, AP-HM, Conception Hospital, Marseille, France.
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Farnault
Aix-Marseille Université, INSERM, UMR1090, TAGC Campus, Marseille, France.
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Nguyen
Hematology laboratory, APHM, Hôpital de la Conception, Marseille, France.
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Brunet
Advanced BioDesign, Lyon, France.
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Ceylan
Aix-Marseille Université, INSERM, UMR1090, TAGC Campus, Marseille, France.|Department of Hematology and Cellular therapy, AP-HM, Conception Hospital, Marseille, France.
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Costello
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000480:Alkynes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D002648:Child; D004195:Disease Models, Animal; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D008297:Male; D051379:Mice; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D010641:Phenotype; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
D000480:Alkynes; D015415:Biomarkers; D013438:Sulfhydryl Compounds; C466361:dimethylthioampal; D000444:Aldehyde Dehydrogenase; D020169:Caspases