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Title: Identification and characterisation of the haematopoietic stem/progenitor cells at risk for leukaemia development following radiation exposure
Author: Verbiest, Tom
ISNI:       0000 0004 6421 7073
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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A variety of epidemiological studies have provided support for an increased leukaemia incidence following exposure to both high and low dose radiation. There is a close histopathological similarity between human and murine acute myeloid leukaemia with mouse models of the disease being most often used. We report here, for the first time, that allogeneic haematopoietic stem cells can compete for niches in the nonmyeloablated NSG bone marrow compartment and that the nonmyeloablated NSG bone marrow microenvironment is capable of supporting allogeneic long-term HSC engraftment and differentiation. Using this NSG transplantation model, we then provided evidence of a reduced contribution of low dose irradiated HSCs towards longterm haematopoiesis. We further report on the generation and characterisation of a novel Chr2MDRmCh mouse model where a construct positioned in the minimal deleted region following radiation exposure carries the fluorescent protein mCherry, which is expressed under control of the ubiquitous Rosa26 promoter. Crossing these mice with Sfpi1GFP mice allowed the early detection of an expanding haematopoietic clone which had lost mCherry fluorescence following radiation exposure (and so also the chromosome 2 homologue carrying the fluorescent construct and the Sfpi1 gene). Finally, we report on a gender-dependent leukaemic progression and characterisation where 3 Gy irradiated male mice only present with acute myeloid leukemia and irradiated female mice mainly develop leukaemia with a lymphoid phenotype. In conclusion, the work in this thesis postulates data obtained from two novel mouse models and which could help to further identify key molecular mechanisms involved in leukaemia initiation and development.
Supervisor: O'Neill, Peter ; Badie, Christophe Sponsor: Public Health England
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available