The analysis of Bcr-Abl—Nox signalling in chronic myeloid leukaemia

Show simple item record

dc.contributor.advisor Cotter, Thomas G. en
dc.contributor.author Landry, William D.
dc.date.accessioned 2014-04-02T15:36:32Z
dc.date.available 2014-04-02T15:36:32Z
dc.date.issued 2013
dc.date.submitted 2013
dc.identifier.citation Landry, W.D. 2013. The analysis of Bcr-Abl—Nox signalling in chronic myeloid leukaemia. PhD Thesis, University College Cork. en
dc.identifier.endpage 239
dc.identifier.uri http://hdl.handle.net/10468/1503
dc.description.abstract Chronic Myeloid Leukaemia (CML) is a myeloproliferative disorder characterised by increased proliferation of haematopoietic stem cells. CML results following generation of the chimeric protein Bcr-Abl, a constitutively active tyrosine kinase which induces oncogenesis in part by promoting increased cell survival and proliferation. Since the development of Bcr-Abl-specific tyrosine kinase inhibitors (TKIs) there has been a substantial improvement in the clinical treatment of CML. Unfortunately, residual disease and the development of TKI resistance has become an ever growing concern, resulting in the need for a greater understanding of the disease in order to develop new treatment strategies. Interestingly, constitutive expression of the Bcr-Abl in CML is known to produce elevated levels of Reactive Oxygen Species (ROS) which are known to influence a variety of cellular processes. Previous studies have demonstrated that NADPH oxidase (Nox) activity contributes to intracellular-ROS levels in Bcr-Abl-positive cells, enhancing survival signalling. The objective of this study was to elucidate how Nox protein activity was influenced downstream of Bcr-Abl while examining how Nox-derived ROS influenced CML disease phenotype to identify the potential in targeting these proteins to improve CML treatment. These studies demonstrated that inhibition of Bcr-Abl signalling, led to a significant reduction in ROS levels which was concurrent with the GSK-3dependent, post-translational down-regulation of the small membrane-bound protein p22phox, an essential component of the Nox complex. siRNA knockdown of p22phox identified it to have a significant role in cellular proliferation and cell viability, demonstrating the importance of Nox protein activity in CML disease phenotype. Furthermore, removal of p22phox was demonstrated to make cells significantly more susceptible to Bcr-Abl-specific TKI treatment, while pharmacological silencing of Nox activity in combination with TKIs was demonstrated to produce substantial, synergistic increases in cell death through augmentation of apoptosis, demonstrating the therapeutic potential of targeting Nox proteins in combination with Bcr-Abl inhibition. en
dc.description.sponsorship Irish Cancer Society (CRS10LAN) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2013, William D. Landry en
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/3.0/ en
dc.subject Bcr-Abl en
dc.subject Nox en
dc.subject p22phox en
dc.subject Imatinib en
dc.subject Combination en
dc.subject Nilotinib en
dc.subject ROS en
dc.subject DPI en
dc.subject CML en
dc.subject Chronic myeloid leukaemia en
dc.subject Reactive oxygen species en
dc.subject NADPH oxidase en
dc.subject.lcsh Leukemia en
dc.subject.lcsh Cell interaction en
dc.title The analysis of Bcr-Abl—Nox signalling in chronic myeloid leukaemia en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD (Science) en
dc.internal.availability Full text available en
dc.check.info No embargo required en
dc.description.version Accepted Version
dc.contributor.funder Irish Cancer Society en
dc.description.status Not peer reviewed en
dc.internal.school Biochemistry en
dc.check.type No Embargo Required
dc.check.reason No embargo required en
dc.check.opt-out Not applicable en
dc.thesis.opt-out false
dc.check.embargoformat Not applicable en
ucc.workflow.supervisor t.cotter@ucc.ie
dc.internal.conferring Summer Conferring 2014


Files in this item

This item appears in the following Collection(s)

Show simple item record

© 2013, William D. Landry Except where otherwise noted, this item's license is described as © 2013, William D. Landry
This website uses cookies. By using this website, you consent to the use of cookies in accordance with the UCC Privacy and Cookies Statement. For more information about cookies and how you can disable them, visit our Privacy and Cookies statement