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Title: Unravelling the molecular and cellular mechanisms of fetal B cell lymphopoiesis to help understand childhood leukaemia
Author: Green, Joanna A. C.
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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Childhood Leukaemia accounts for nearly one in three of all childhood cancers, with approximately 400 cases diagnosed in the UK every year. Initial genetic lesions in paediatric and infant B cell leukaemias occur in utero in fetal haematopoietic progenitors. Despite the importance of understanding fetal B cell lymphopoiesis in relation to the aetiology of leukaemia, fetal B cell development remains poorly characterised. We hypothesised that by understanding and characterising murine fetal B cell lymphopoiesis, we would gain insights into the development of childhood leukaemias. In chapter III of this thesis I show that the first immune restricted cells with B cell potential in the mouse emerge in the E9.5 vascular plexus of the yolk sac. Subsequently, in chapter IV, I use a Mb1-cre fate mapping approach to show that progenitors which are entirely restricted to the B cell lineage can be detected as early as E12.5 in the fetal liver (FL), prior to the cell surface expression of CD19. In chapter V, I investigate B cell progenitors in the E14.5 FL, applying an advanced B cell staging originally developed for the adult bone marrow, modified to include the key lymphoid cytokine receptors IL-7Ra, KIT and FLT3. I identify and functionally and molecularly characterise a rare CD19+ B cell progenitor that expresses FLT3 and peaks in frequency in late gestation embryos. I further show that FLT3+ CD19+ adult Pro B cells demonstrate an increased engraftment when transplanted into recipient mice compared to CD19+FLT3- Pro B cells. Finally in chapter VI, I apply our new understanding of fetal B cell lymphopoiesis to characterise B cell progenitors in a mouse that expresses the TEL-AML1 translocation, an oncogene associated with 25% of paediatric B cell leukaemias. We find that the novel FLT3+ CD19+ ProB cell progenitor identified here is expanded in the fetal liver of E14.5 TEL-AML1 embryos, giving a new developmental insight into the functional impact of this oncogene.
Supervisor: Jacobsen, Sten Eirik ; Boiers, Charlotta Sponsor: Alexander Thatte Fund ; De Breyne Scholarship
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available