title: Autophagy: friend or foe in the treatment of fusion protein-associated leukemias?
abstract: Both radiation and chemotherapeutic drugs induce autophagy in tumor cells, and whether this contributes to cell death or survival is debated. Although a prodeath role has been reported in certain contexts, treatment-induced autophagy often exerts a prosurvival function by preventing apoptosis and delaying necrosis. Interestingly, a more specific role of autophagy has been demonstrated in certain subtypes of leukemia. The fusion oncoproteins PML-RARA and BCR-ABL, the main oncogenic drivers of acute promyelocytic leukemia and chronic myeloid leukemia (CML), respectively, have recently been identified as autophagy substrates and their degradation by autophagy shown to contribute to treatment. However, this does not seem to be a general feature of leukemic fusion oncoproteins, as we recently found that AML1-ETO, the most frequently occurring acute myeloid leukemia (AML) fusion protein, is not an autophagy substrate. Rather we demonstrate a clear prosurvival role of autophagy in this AML subtype and that addition of autophagy inhibitors in the treatment regimen might be beneficial.
authors.affiliation: Institute of Basic Medical Sciences; University of Oslo; Oslo, Norway.
authors.forename: Maria Lyngaas
authors.initials: ML
authors.lastname: Torgersen
authors.forename: Anne
authors.initials: A
authors.lastname: Simonsen
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D000075142:RUNX1 Translocation Partner 1 Protein
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D056572:Histone Deacetylase Inhibitors; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D016044:Fusion Proteins, bcr-abl
keywords: AML; AML1-ETO; BCR-ABL; PML-RARA; autophagy; chloroquine; leukemia; valproic acid; vorinostat