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Small molecule mediated targeting of haematopoietic stem/progenitor cell and leukaemic stem cell function

Saleh, Lubaid 2017. Small molecule mediated targeting of haematopoietic stem/progenitor cell and leukaemic stem cell function. PhD Thesis, Cardiff University.
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Abstract

Haematopoietic stem cells (HSC) are a rare population of cells that have the ability to self-renew and differentiate giving rise to various blood lineages, thereby reconstituting the whole haematopoietic system. This is an essential characteristic, exploited in bone marrow transplantation therapy in response to myeloablative treatment. Due to their rarity, the lack of sufficient HSC numbers for transplantation has proved to be a major clinical issue. Separately, in the development of leukaemia, acquired mutations in HSCs give rise to malignant cells. These cells, like HSCs, have the ability to self-renew and differentiate forming immature blasts and are termed cancer (leukaemic) stem cells. They are thought to remain in a quiescent state and are therefore not targeted by standard chemotherapy, inducing relapse in haematopoietic malignancies. In this study, a cross species stem cell based screen was conducted on a 12,000 small molecule library across a range of adult and embryonic tissue types with a view to identifying compounds that would (i) expand HSCs ex vivo and in vivo for transplantation and (ii) eradicate cancer stem cells in leukaemia. A number of small molecules were identified as lead compounds and were assessed in our investigation. We found that Yohimbine, an alpha-2 adrenergic receptor (adra-2) antagonist, and Oxa-22, cis-2-Methyl-5-trimethylammoniummethyl-1,3-oxathiolane iodide (M3 Muscarinic acetylcholine receptor agonist) elicited a 2- and 1.5- fold increase in HSC frequency (respectively) in vivo. Further competitive transplantation studies showed that Yohimbine and Oxa-22 treated cells also enhanced the reconstitution of B cells and T cells respectively. In parallel, we also assessed Oxa-22 and a third compound, Phthalylsulfathiazole- an antibacterial sulphonamide, in the leukaemic setting to ascertain whether compounds could target leukaemic stem cells (LSCs). We found that these compounds promoted proliferation in acute myeloid leukaemia (AML) cell lines. Furthermore, when Oxa-22 and Phthalylsulfathiazole were administered in vivo models of AML, they accelerated disease progression by increasing the number of LSCs. Collectively, these results show that using small molecules we can target neuronal related pathways to enhance HSC number and function. Further investigation is required to elucidate the exact mechanisms of the compounds however, these data may prove to be influential in directing new methods of stem cell expansion for transplantation therapies. Small molecules targeting neuronal or antibacterial related pathways were also found to target malignant LSCs and alter their behaviour. By driving LSCs out of their dormant state, these small molecules may pave the way for potential targeting of LSCs in conjuction with standard current chemotherapies that incorporate and kill proliferating cancer cells.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Biosciences
Date of First Compliant Deposit: 4 October 2017
Last Modified: 08 Nov 2018 02:30
URI: http://orca.cf.ac.uk/id/eprint/105172

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