FLT3-driven redox signalling in acute myeloid leukaemia

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dc.contributor.advisor Cotter, Thomas G.
dc.contributor.author Corcoran, Aoife
dc.date.accessioned 2013-02-14T13:41:53Z
dc.date.available 2013-02-14T13:41:53Z
dc.date.issued 2013-01
dc.date.submitted 2013-01-16
dc.identifier.citation Cororan, A., 2013. FLT3-driven redox signalling in acute myeloid leukaemia. PhD Thesis, University College Cork. en
dc.identifier.uri http://hdl.handle.net/10468/962
dc.description.abstract Acute myeloid leukaemia refers to cancer of the blood and bone marrow characterised by the rapid expansion of immature blasts of the myeloid lineage. The aberrant proliferation of these blasts interferes with normal haematopoiesis, resulting in symptoms such as anaemia, poor coagulation and infections. The molecular mechanisms underpinning acute myeloid leukaemia are multi-faceted and complex, with a range of diverse genetic and cytogenetic abnormalities giving rise to the acute myeloid leukaemia phenotype. Amongst the most common causative factors are mutations of the FLT3 gene, which codes for a growth factor receptor tyrosine kinase required by developing haematopoietic cells. Disruptions to this gene can result in constitutively active FLT3, driving the de-regulated proliferation of undifferentiated precursor blasts. FLT3-targeted drugs provide the opportunity to inhibit this oncogenic receptor, but over time can give rise to resistance within the blast population. The identification of targetable components of the FLT3 signalling pathway may allow for combination therapies to be used to impede the emergence of resistance. However, the intracellular signal transduction pathway of FLT3 is relatively obscure. The objective of this study is to further elucidate this pathway, with particular focus on the redox signalling element which is thought to be involved. Signalling via reactive oxygen species is becoming increasingly recognised as a crucial aspect of physiological and pathological processes within the cell. The first part of this study examined the effects of NADPH oxidase-derived reactive oxygen species on the tyrosine phosphorylation levels of acute myeloid leukaemia cell lines. Using two-dimensional phosphotyrosine immunoblotting, a range of proteins were identified as undergoing tyrosine phosphorylation in response to NADPH oxidase activity. Ezrin, a cytoskeletal regulatory protein and substrate of Src kinase, was selected for further study. The next part of this study established that NADPH oxidase is subject to regulation by FLT3. Both wild type and oncogenic FLT3 signalling were shown to affect the expression of a key NADPH oxidase subunit, p22phox, and FLT3 was also demonstrated to drive intracellular reactive oxygen species production. The NADPH oxidase target protein, Ezrin, undergoes phosphorylation on two tyrosine residues downstream of FLT3 signalling, an effect which was shown to be p22phox-dependent and which was attributed to the redox regulation of Src. The cytoskeletal associations of Ezrin and its established role in metastasis prompted the investigation of the effects of FLT3 and NADPH oxidase activity on the migration of acute myeloid leukaemia cell lines. It was found that inhibition of either FLT3 or NADPH oxidase negatively impacted on the motility of acute myeloid leukaemia cells. The final part of this study focused on the relationship between FLT3 signalling and phosphatase activity. It was determined, using phosphatase expression profiling and real-time PCR, that several phosphatases are subject to regulation at the levels of transcription and post-translational modification downstream of oncogenic FLT3 activity. In summary, this study demonstrates that FLT3 signal transduction utilises a NADPH oxidase-dependent redox element, which affects Src kinase, and modulates leukaemic cell migration through Ezrin. Furthermore, the expression and activity of several phosphatases is tightly linked to FLT3 signalling. This work reveals novel components of the FLT3 signalling cascade and indicates a range of potential therapeutic targets. en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.relation.uri http://dx.doi.org/10.1158/1538-7445.AM2012-2545
dc.relation.uri http://dx.doi.org/10.3109/10715762.2012.733385
dc.relation.uri http://online.liebertpub.com/doi/abs/10.1089/ars.2012.5028
dc.rights © 2013, Aoife Corcoran en
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/3.0/ en
dc.subject Redox en
dc.subject FLT3 en
dc.subject Leukaemia en
dc.subject ROS en
dc.subject NADPH oxidase en
dc.subject.lcsh Myeloid leukemia--Treatment en
dc.title FLT3-driven redox signalling in acute myeloid leukaemia en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD Scholars Programme in Cancer Biology en
dc.internal.availability Full text available en
dc.description.version Accepted Version en
dc.contributor.funder Health Research Board en
dc.description.status Not peer reviewed en
dc.internal.school Biochemistry and Cell Biology en

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© 2013, Aoife Corcoran Except where otherwise noted, this item's license is described as © 2013, Aoife Corcoran
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