Evaluation of the role of autophagy in acute myeloid leukaemic cell differentiation

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dc.contributor.advisor Cahill, Mary en
dc.contributor.advisor Mongan, Nigel en
dc.contributor.advisor Gudas, Lorraine en
dc.contributor.advisor McKenna, Sharon L. en
dc.contributor.author Orfali, Nina
dc.date.accessioned 2017-06-19T11:19:48Z
dc.date.available 2017-06-19T11:19:48Z
dc.date.issued 2017
dc.date.submitted 2017
dc.identifier.citation Orfali, N. 2017. Evaluation of the role of autophagy in acute myeloid leukaemic cell differentiation. PhD Thesis, University College Cork. en
dc.identifier.uri http://hdl.handle.net/10468/4089
dc.description.abstract Acute myeloid leukemia (AML) is a malignancy characterized by the accumulation of white blood cell precursors in the bone marrow and circulation. Treatment regimens for this disease are notoriously toxic and survival is poor. Pharmacological overcoming the differentiation block seen in AML is an attractive avenue of therapy, termed ‘differentiation therapy’. The best example of this is the use of all-trans-retinoic acid (ATRA) in the treatment of acute promyelocytic leukaemia (APL). The differentiation of APL cells treated with ATRA in vitro is a model that allows the examination of differentiation pathways in myeloid leukaemic cells. Using this principle, my thesis examines the activity during differentiation, of two pathways involved in post-translational protein handling - autophagy and ISGylation. Autophagy is an intracellular recycling pathway responsible for degrading aged or redundant proteins. I demonstrate that ATRA induces autophagy and this has a functional role in differentiation. Autophagy inhibition reduces myeloid differentiation while pharmacologic induction may promote differentiation in ATRA-resistant cells. Using next-generation sequencing, I explore the molecular communication between retinoids and autophagy and study the expression changes in autophagy-related genes occurring in ATRAtreated APL cells. I also demonstrate that ISGylation is activated during differentiation, a process regulating the addition of a ubiquitin-like modifier, interferonstimulated gene 15 (ISG15) to target proteins. Targeted inhibition of ISGylation impedes differentiation. I discuss the benefits and practical implications of pharmacologically targeting both autophagy and ISGylation. A thorough molecular understanding of these pathways might broaden the application of differentiation therapy to other AML subtypes. en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2017, Nina Orfali. en
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/3.0/ en
dc.subject Autophagy en
dc.subject Differentiation en
dc.subject ISGylation en
dc.subject Acute myeloid leukaemia en
dc.title Evaluation of the role of autophagy in acute myeloid leukaemic cell differentiation en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD (Medicine and Health) en
dc.internal.availability Full text not available en
dc.check.info No embargo required en
dc.description.version Accepted Version
dc.description.status Not peer reviewed en
dc.internal.school Medicine en
dc.check.type No Embargo Required
dc.check.reason No embargo required en
dc.check.opt-out Yes en
dc.thesis.opt-out true
dc.check.embargoformat Not applicable en
dc.internal.conferring Summer 2016 en

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© 2017, Nina Orfali. Except where otherwise noted, this item's license is described as © 2017, Nina Orfali.
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