title: Induction of autophagy is a key component of all-trans-retinoic acid-induced differentiation in leukemia cells and a potential target for pharmacologic modulation.
abstract: Acute myeloid leukemia (AML) is characterized by the accumulation of immature blood cell precursors in the bone marrow. Pharmacologically overcoming the differentiation block in this condition is an attractive therapeutic avenue, which has achieved success only in a subtype of AML, acute promyelocytic leukemia (APL). Attempts to emulate this success in other AML subtypes have thus far been unsuccessful. Autophagy is a conserved protein degradation pathway with important roles in mammalian cell differentiation, particularly within the hematopoietic system. In the study described here, we investigated the functional importance of autophagy in APL cell differentiation. We found that autophagy is increased during all-trans-retinoic acid (ATRA)-induced granulocytic differentiation of the APL cell line NB4 and that this is associated with increased expression of LC3II and GATE-16 proteins involved in autophagosome formation. Autophagy inhibition, using either drugs (chloroquine/3-methyladenine) or short-hairpin RNA targeting the essential autophagy gene ATG7, attenuates myeloid differentiation. Importantly, we found that enhancing autophagy promotes ATRA-induced granulocytic differentiation of an ATRA-resistant derivative of the non-APL AML HL60 cell line (HL60-Diff-R). These data support the development of strategies to stimulate autophagy as a novel approach to promote differentiation in AML.
authors.affiliation: Cork Cancer Research Centre, Leslie C. Quick, Jr., Laboratory, Biosciences Institute, University College Cork, Cork, Ireland; Department of Hematology, Cork University Hospital, Cork, Ireland; Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Orfali
authors.affiliation: Cork Cancer Research Centre, Leslie C. Quick, Jr., Laboratory, Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Tracey R
authors.initials: TR
authors.lastname: O'Donovan
authors.affiliation: Cork Cancer Research Centre, Leslie C. Quick, Jr., Laboratory, Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Nyhan
authors.affiliation: Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Adrian
authors.initials: A
authors.lastname: Britschgi
authors.affiliation: Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Mario P
authors.initials: MP
authors.lastname: Tschan
authors.affiliation: Department of Hematology, Cork University Hospital, Cork, Ireland.
authors.forename: Mary R
authors.initials: MR
authors.lastname: Cahill
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA; Faculty of Medicine and Health Science, School of Veterinary Medicine and Science, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Mongan
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Lorraine J
authors.initials: LJ
authors.lastname: Gudas
authors.affiliation: Cork Cancer Research Centre, Leslie C. Quick, Jr., Laboratory, Biosciences Institute, University College Cork, Cork, Ireland. Electronic address: s.mckenna@ucc.ie.
authors.forename: Sharon L
authors.initials: SL
authors.lastname: McKenna
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018501:Antirheumatic Agents / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D000071193:Autophagy-Related Protein 7; D000071190:Autophagy-Related Protein 8 Family; D002454:Cell Differentiation / Q000187:drug effects*; D002738:Chloroquine / Q000494:pharmacology; D006098:Granulocytes / Q000378:metabolism / Q000473:pathology; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D018501:Antirheumatic Agents; D000071190:Autophagy-Related Protein 8 Family; C498698:GABARAPL2 protein, human; C477012:MAP1LC3A protein, human; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; C025946:3-methyladenine; D014212:Tretinoin; D002738:Chloroquine; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes; D000225:Adenine