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

Simple item page
dc.check.embargoformatNot applicableen
dc.check.infoNo embargo requireden
dc.check.opt-outNot applicableen
dc.check.reasonNo embargo requireden
dc.check.typeNo Embargo Required
dc.contributor.advisorCotter, Thomas G.en
dc.contributor.authorLandry, William D.
dc.contributor.funderIrish Cancer Societyen
dc.date.accessioned2014-04-02T15:36:32Z
dc.date.available2014-04-02T15:36:32Z
dc.date.issued2013
dc.date.submitted2013
dc.description.abstractChronic 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.sponsorshipIrish Cancer Society (CRS10LAN)en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationLandry, W.D. 2013. The analysis of Bcr-Abl—Nox signalling in chronic myeloid leukaemia. PhD Thesis, University College Cork.en
dc.identifier.endpage239
dc.identifier.urihttps://hdl.handle.net/10468/1503
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2013, William D. Landryen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectBcr-Ablen
dc.subjectNoxen
dc.subjectp22phoxen
dc.subjectImatiniben
dc.subjectCombinationen
dc.subjectNilotiniben
dc.subjectROSen
dc.subjectDPIen
dc.subjectCMLen
dc.subjectChronic myeloid leukaemiaen
dc.subjectReactive oxygen speciesen
dc.subjectNADPH oxidaseen
dc.subject.lcshLeukemiaen
dc.subject.lcshCell interactionen
dc.thesis.opt-outfalse
dc.titleThe analysis of Bcr-Abl—Nox signalling in chronic myeloid leukaemiaen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD (Science)en
ucc.workflow.supervisort.cotter@ucc.ie
Files
Original bundle
Now showing 1 - 2 of 2
Thumbnail Image
Name:
Thesis.pdf
Size:
4.63 MB
Format:
Adobe Portable Document Format
Description:
Full Text E-Thesis
Download
Thumbnail Image
Name:
Abstract.pdf
Size:
19.3 KB
Format:
Adobe Portable Document Format
Description:
Abstract
License bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
license.txt
Size:
5.62 KB
Format:
Item-specific license agreed upon to submission
Description:
Download
Collections
Doctoral Theses
Biochemistry and Cell Biology - Doctoral Theses
College of Science, Engineering and Food Science - Doctoral Theses