Proteasome inhibition in chronic myeloid leukaemia

Heaney, Nicholas Benjamin (2009) Proteasome inhibition in chronic myeloid leukaemia. MD thesis, University of Glasgow.

Abstract

CML is treated effectively with TKI, however two key problems remain - the insensitivity of CM HSC to TKI and the emergence of TKI-resistant BCR-ABL mutations. BCR-ABL activity is associated with increased proteasome activity and PI are cytotoxic against CML cell lines. We demonstrate that bortezomib is antiproliferative and induces apoptosis in CD34+ cells taken at diagnosis from patients with CP CML cells, with an LD50 below concentrations achieved in vivo. We also demonstrate for the first time that CD34+38- CML cells, representing the TKI-insensitive primitive HSC, are similarly susceptible. Bortezomib is associated with inhibition of proteasome activity, however that of BCR-ABL appears unaffected. Significant synergy is seen when bortezomib and dasatinib are used in combination. We also demonstrate that bortezomib is effective in inhibiting proteasome activity and inducing apoptosis in cell lines expressing BCR-ABL mutations, including T315I. Therefore we believe that bortezomib offers a potential therapeutic option in CML by targeting both TKI-insensitive stem cells and TKI-resistant BCR-ABL mutations.

• Item Type: Thesis (MD)
• Qualification Level: Doctoral
• Keywords: chronic myeloid leukaemia, proteasome inhibitor, tyrosine kinase inhibitor, stem cell
• Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer); R Medicine > RM Therapeutics. Pharmacology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Supervisor's Name: Holyoake, Professor Tessa
• Date of Award: 2009
• Depositing User: Dr Nicholas Benjamin Heaney
• Unique ID: glathesis:2009-832
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 23 Jun 2009
• Last Modified: 10 Dec 2012 13:26
• URI: https://theses.gla.ac.uk/id/eprint/832