Uncovering the BCR-ABL1 tyrosine kinase independent signature in chronic myeloid leukaemia stem cells

Gómez-Castañeda, Eduardo (2018) Uncovering the BCR-ABL1 tyrosine kinase independent signature in chronic myeloid leukaemia stem cells. PhD thesis, University of Glasgow.

Due to Embargo and/or Third Party Copyright restrictions, this thesis is not available in this service.

Abstract

Chronic myeloid leukaemia (CML) is characterised by the presence of the fusion protein BCR-ABL1. The addiction of CML cells to the tyrosine kinase (TK) activity of the oncoprotein has been successfully exploited by the introduction of tyrosine kinase inhibitors (TKI), such as imatinib, which have shown a great success at managing the disease. However, these compounds fail to eradicate a primitive cell population, the leukaemic stem cells (LSCs), which persist in the patients. This translates in the need of life-long therapy for most of the patients, meaning a higher risk of treatment side effects and the prolonged psychological burden of living a leukaemia patient. Life-long therapy is also translating in a continuous increase in CML prevalence in developed countries and sustaining a big patient population on TKI treatment is becoming a challenge for national health systems.
Recent reports in chronic myeloid leukaemia biology have confirmed that CML LSCs are not addicted to the TK activity of BCR-ABL1 and they retain repopulation and leukaemic properties even during BCR-ABL1 TK inhibition. Thus, the discovery of new therapeutic targets capable of eliminating this cell population is required for curing the disease. Previous reports have already shown great success at reducing the number of CML LSCs by targeting JAK2, STAT5, EZH2, MYC and p53 pathways as well as autophagocytosis. However, none of them have shown complete eradication of the clone and they failed to define a global gene expression signature that may explain the persistence of CML LSCs during TKI treatment.
Taken together, the work presented in this thesis confirms the existence of a BCR-ABL1 transcriptional signature in CML LSCs. Also, it shows that targeting CD33, a member of the TKIi signature, reduces the number of CML CD34+ cells and induces a transcriptional and phenotypic change towards a cycling and repopulating cell population. Additionally, the use of the TKIi signature has shown potential as a molecular biomarker for predicting TKI response in CML patients.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: CML, chronic myeloid leukaemia, leukaemia, haematology, cancer, bioinformatics, BCR-ABL1, TKI.
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences > Paul O'Gorman Leukemia Research Centre
Supervisor's Name: Jørgensen, Dr. Heather and Rogers, Dr. Simon and Hopcroft, Dr. Lisa and Holyoake, Prof. Tessa
Date of Award: 2018
Embargo Date: 3 January 2022
Depositing User: Eduardo Gómez-Castañeda
Unique ID: glathesis:2018-39043
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 29 Jan 2019 15:26
Last Modified: 29 Jan 2019 15:26
URI: http://theses.gla.ac.uk/id/eprint/39043
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