An investigation into the chronic myeloid leukaemia bone marrow microenvironment

Dawson, Amy Elizabeth Margaret (2020) An investigation into the chronic myeloid leukaemia bone marrow microenvironment. PhD thesis, University of Glasgow.

Abstract

Chronic myeloid leukaemia (CML) is a myeloproliferative neoplasm that arises due to the formation of a fusion oncogene, BCR-ABL1, in a haematopoietic stem cell (HSC). Once considered a fatal disease, the treatment of CML has drastically improved over the past 20 years due to the introduction of tyrosine kinase inhibitors (TKI). However, most patients remain on TKI therapy for life and are not cured of their disease due to persistence and therapy resistance of the leukaemic stem cell (LSC).

A plethora of literature has focussed on targeting the CML LSC, with the ultimate goal of elimination and cure of CML. However, to date, no single drug has been successfully implemented in the clinic to eradicate CML LSCs and allow for TKI discontinuation. Identification of targetable pathways in the LSC remains a promising approach to CML research. However, understanding the bone marrow (BM) environment, and LSC supportive mechanisms will allow one to more clearly understand how the LSC persists and potentially identify novel therapeutic interventions.
The BM niche is essential to the support of the HSC survival, quiescence and proliferative potential, yet in CML, the niche is altered to favour support of the LSC. This investigation aimed to understand in more detail the interaction between the BM microenvironment and CML LSCs. Specifically, the aim was to identify the impact of a low oxygen environment on LSC metabolism and secondly, investigate the interaction between CML cells and macrophages, a population of cells essential to normal HSC function.

Here these results demonstrate that the metabolic response of CD34+ CML cells is independent of their response to TKI treatment. This analysis revealed that CML cells increase their expression of PFK-2 family enzymes in hypoxia to a greater extent than normal CD34+ cells. However, loss of PFKFB4 did not appear to be essential to CML survival or metabolic adaptation to hypoxia.

Addressing the second aim, it was found that murine CML stem/progenitor cells have a significantly dysregulated secretome and macrophages exposed to this environment have an altered phenotype. Finally, our findings demonstrate that the CML microenvironment has a significant impact on the cellular composition of the niche in vivo.

Overall, these results indicate there is a close relationship between CML stem/progenitor cells and the niche. Hypoxia regulates distinct metabolic pathways in CML that can be potentially exploited therapeutically. Finally, this investigation presents novel findings that CML stem/progenitor cells have a dysregulated secretome that directly modifies niche macrophages.

• Item Type: Thesis (PhD)
• Keywords: CML; microenvironment; bone marrow; niche; leukaemia
• Subjects: Q Science > Q Science (General); Q Science > QH Natural history > QH301 Biology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences > Paul O'Gorman Leukemia Research Centre
• Supervisor's Name: Helgason, Dr Vignir
• Date of Award: 2020
• Embargo Date: 15 May 2023
• Depositing User: Miss Amy Dawson
• Unique ID: glathesis:2020-81366
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 15 May 2020 14:38
• Last Modified: 15 May 2020 14:38
• URI: https://theses.gla.ac.uk/id/eprint/81366