title: Targeting autophagy potentiates the apoptotic effect of histone deacetylase inhibitors in t(8;21) AML cells.
abstract: The role of autophagy during leukemia treatment is unclear. On the one hand, autophagy might be induced as a prosurvival response to therapy, thereby reducing treatment efficiency. On the other hand, autophagy may contribute to degradation of fusion oncoproteins, as recently demonstrated for promyelocytic leukemia-retinoic acid receptor α and breakpoint cluster region-abelson, thereby facilitating leukemia treatment. Here, we investigated these opposing roles of autophagy in t(8;21) acute myeloid leukemia (AML) cells, which express the most frequently occurring AML fusion oncoprotein, AML1-eight-twenty-one (ETO). We demonstrate that autophagy is induced by AML1-ETO-targeting drugs, such as the histone deacetylase inhibitors (HDACis) valproic acid (VPA) and vorinostat. Furthermore, we show that autophagy does not mediate degradation of AML1-ETO but rather has a prosurvival role in AML cells, as inhibition of autophagy significantly reduced the viability and colony-forming ability of HDACi-treated AML cells. Combined treatment with HDACis and autophagy inhibitors such as chloroquine (CQ) led to a massive accumulation of ubiquitinated proteins that correlated with increased cell death. Finally, we show that VPA induced autophagy in t(8;21) AML patient cells, and combined treatment with CQ enhanced cell death. Because VPA and CQ are well-tolerated drugs, combinatorial therapy with VPA and CQ could represent an attractive treatment option for AML1-ETO-positive leukemia.
authors: Department of Biochemistry, Institute of Basic Medical Sciences, Faculty of Medicine, and.
authors: Maria Lyngaas
authors: ML
authors: Torgersen
authors: Nikolai
authors: N
authors: Engedal
authors: Stig-Ove
authors: SO
authors: Bøe
authors: Peter
authors: P
authors: Hokland
authors: Anne
authors: A
authors: Simonsen
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology; D002898:Chromosomes, Human, Pair 8; D050676:Core Binding Factor Alpha 2 Subunit; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D015151:Immunoblotting; D015470:Leukemia, Myeloid, Acute; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D014162:Transfection; D014635:Valproic Acid / Q000494:pharmacology; D000077337:Vorinostat
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D000077337:Vorinostat; D014635:Valproic Acid; D002738:Chloroquine