Investigating a co-operative link between TGF-β and Lyn kinase in Chronic Myeloid Leukaemia

Smith, Paul (2011) Investigating a co-operative link between TGF-β and Lyn kinase in Chronic Myeloid Leukaemia. Doctoral thesis, University of East Anglia.

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Chronic myeloid leukaemia (CML) is a myeloproliferative disorder characterised by uncontrolled proliferation of haematopoietic cells driven by the fusion gene Bcr-Abl. The advent of a mechanism specific kinase inhibitor, Imatinib, targeting the constitutively active Bcr-Abl kinase has paved the way for new treatment strategies. However, resistance emerges, particularly in those in more advanced disease stages. One factor in this resistance is the presence of a quiescent subset of CML cells that are insensitive to Imatinib. CML resistance to Imatinib is linked with over-expression and activation of Lyn, a member of the Src family kinases (SFK). The main aim of the project was to investigate whether transforming growth factor-β (TGF) might influence drug-resistance through direct affects on Lyn kinase levels and its activation.
This research builds on previous findings of Bcr-Abl-dependent up-regulation of TGFβ signalling, implicating this cytokine in CML. Human MYL cell lines derived from a CML patient were used to show TGFβ plays a role in imatinib-resistance through direct effects on Lyn protein turnover. Stimulation of MYL cells with TGFβ produced cyclic changes in high molecular weight bands in the presence of proteasomal inhibitors. These high molecular weight bands are due to TGF inducing Lyn ubiquitination, and that this is mediated via TGF-dependent expression of the c-cbl E3 ubiquitin ligase. Cell cycle analysis in combination with poly ADP ribose polymerase (PARP) cleavage assays show TGFβ causes cell quiescence, and that the inhibition of the signalling pathway releases cells from growth arrest and enhances Imatinib-induced cell death. Collectively, data highlights a potential new dual-treatment approach using a combination of Imatinib and SB431542 to enhance imatinib-mediated cell death in
CML. Furthermore, it is speculated that hyper-activation of the TGF pathway in the presence of Bcr-Abl drives CML drug resistance by a co-operative mechanism involving Lyn kinase ubiquitination and activation, which is linked to the c-cbl proto-oncogene.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Biological Sciences
Depositing User: Megan Ruddock
Date Deposited: 19 Jun 2012 10:26
Last Modified: 27 Jan 2015 16:51


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