Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.696334
Title: Identification of activated pathways following epigenetic combination therapies in myeloid leukaemia cell lines
Author: Young , Christine Samantha
ISNI:       0000 0004 5992 7898
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2015
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Abstract:
Acute myeloid leukaemia is a heterogeneous clonal disorder of myeloid progenitor cells and primarily a disease of the elderly. Advances in treatment regimens have significantly improved survival rates of younger patients however many elderly patients still fail to respond to such intensive treatment approaches highlighting the need for better tolerated therapies. Aberrant epigenetic mechanisms such as methylation and acetylation are known to contribute to AML progression. The development of epigenetic modifying agents provides a means of targeting these mechanisms and although they are known to produce synergy when combined, the underlying molecular mechanisms have yet to be fully characterised. This study therefore aimed to; validate the synergistic mechanisms of action of Decitabine combined with Vorinostat, identify a unique gene expression signature following combination treatment and assess whether this could provide further opportunities for improving the use of Decitabine / Vorinostat combination for treating AML. Following sequential combination treatment in a panel of AML cell lines, a number of synergistic effects were observed including decreases in cell viability, induction of apoptosis, enhanced caspase activity and a greater reduction of DNMT1 protein. No further decrease in L1NE-1 methylation was observed. Gene expression profiling and gene ontology analysis identified pathways exclusively enriched following combination treatment (cell death,immune/IFN, cell cycle/DNA replication) providing possible mechanisms for the above synergy. Combination treatment also induced the expression of the receptor tyrosine kinase AXL, over expression of which is associated with a poor prognosis in AML. Ligand stimulation resulted in downstream signalling through AKT. Triple combination studies including an AXL inhibitor also suggest a role for AXL signalling in the QCI-AML3 model. AXL may also induce therapy resistance and be used to predict patient response to this particu(a~r treatment regimen as low expressing AXL cell lines tended to be more sensitive to DecitabineNorinostat treatment. Further work may support a role patient stratification based on AXL expression prior to treatment with the Decitabine / Vorinostat combination in order to select for patients who may respond to this treatment or identify those who may benefit from the addition of an AXL inhibitor.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.696334  DOI: Not available
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