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

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Orfali, Nina
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University College Cork
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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.
Autophagy , Differentiation , ISGylation , Acute myeloid leukaemia
Orfali, N. 2017. Evaluation of the role of autophagy in acute myeloid leukaemic cell differentiation. PhD Thesis, University College Cork.