Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.768678
Title: Uncovering the BCR-ABL1 tyrosine kinase independent signature in chronic myeloid leukaemia stem cells
Author: Gómez-Castañeda, Eduardo
ISNI:       0000 0004 7654 9235
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2018
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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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.768678  DOI:
Keywords: RC0254 Neoplasms. Tumors. Oncology (including Cancer)
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