Unravelling the molecular and cellular mechanisms of fetal B cell lymphopoiesis to help understand childhood leukaemia

Thesis

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-7Rα, 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.

Authors: Green, J

• DOI: 10.5287/ora-o5vwyvbbk
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford