The Role of Autophagy in the Regulation of Quiescence and Survival of Leukaemic Stem Cells
Chronic myeloid leukaemia (CML) develops following a specific mutation in a single blood stem cell. Therefore, these cells serve as crucial target for therapeutic intervention. We have shown that patient-derived quiescent CML stem cells are not eradicated with currently available drugs and can become resistant leading to relapse in patients. Hence, drug combination therapy is required to cure CML. Recently we showed that autophagy (self-eating) affects differentiation, mitochondrial metabolism, reactive oxygen species (ROS) generation, and is an attractive target for CML stem cell eradication. These pre-clinical data led in turn to an on-going clinical trial in which hydroxychloroquine (HCQ)-mediated autophagy inhibition is being tested in CML patients. This is an area of great importance in CML and other stem cell-driven leukaemia types where autophagy inhibition might also improve therapy. The main aim of our proposed research is to further understand how autophagy controls the way in which leukaemic stem cells function - how they stay quiescent and prevent ROS-mediated differentiation, and how they and metabolise nutrients compared to normal cells to escape drug treatment. An additional aim is to use the best laboratory models to test new autophagy inhibitors that have recently been developed. We will use established cell lines and patient-derived cells that have been bio-banked at the Paul O’Gorman Leukaemia Research Centre. Additionally, we will use a state-of-the-art mouse model in which mice develop leukaemia resembling the human disease. This offers an excellent opportunity to investigate autophagy, quiescence and mitochondrial function/metabolism in both normal and leukaemic cells located in the bone marrow. The student will gain significant experience in the isolation of leukaemic stem cells (FACS), survival assays following in vivo/vitro drug treatments, measurement of autophagy (immunofluorescence, live cells imaging, Western blotting), mitochondrial function, ROS levels, DNA damage (immunofluorescence/FACS) and energy metabolism (Mass-spec/Seahorse Extracellular Flux Analyser).
Please send a covering letter and CV, together with degree transcripts and certificates, to the supervisor by Friday 18th December 2015. Please include the name and contact details of two people willing to provide references. Either electronic or postal applications will be accepted - Dr Vignir Helgason, Leadership Fellow, Wolfson Wohl Research Centre, Garscube Estate, Glasgow, G61 1QH
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