Symonds, Janine Delia;
(2023)
Characterisation of Purine Nucleotide Metabolism in an Acute Promyelocytic Leukaemia (APL) cell line using Mathematical Models.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Acute promyelocytic leukaemia (APL) is usually treated using All-trans Retinoic acid (ATRA), but this has potentially life-threatening side effects; prompting the search for novel treatments. Interference with purine metabolism, through inhibition of the enzyme inosine monophosphate dehydrogenase (IMPDH) causes differentiation of HL60 cells, an APL cell line; however, the exact mechanism of action is unknown. Purine metabolism is complex with many internal regulatory mechanisms, thus determining expected outcomes within this system is difficult. The aim of this study was to provide insights into purine metabolism in HL60 cells and investigate the effects of IMPDH inhibition on this system, using a dual approach of mathematical modelling and experimentation. Through refinement and expansion of an existing framework, an HL60 cell specific mathematical model of purine metabolism was established that allows examination of key metabolites. This model is robust with a stable steady state. IMPDH inhibition was simulated and metabolite concentrations were determined. Experimental data was obtained from IMPDH inhibitor treated HL60 cells. Comparison of this data to model output showed low concordance; however this is partly due to the literature data used to refine the model, which this new data also failed to match. Nevertheless, with further refinement the model will be a useful tool in furthering our understanding of purine metabolism in HL60 cells and specifically the effects of IMPDH inhibition. Furthermore, the model could be used to identify other potential novel targets within the purine metabolic network which could be used as new APL therapies. Additionally, this study provides previously uncharacterised data of purine levels in HL60 cells treated with either an IMPDH inhibitor or ATRA alongside guanosine. Furthermore, data showed a synergistic effect on HL60 cell differentiation when ATRA was used alongside an IMPDH inhibitor, raising the possibility of using both drugs together clinically to treat APL.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Characterisation of Purine Nucleotide Metabolism in an Acute Promyelocytic Leukaemia (APL) cell line using Mathematical Models |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Computer Science UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10172594 |
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