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Title: An investigation into the role of MLL in murine haematopoiesis
Author: McMahon, Kathryn Anne
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2007
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The Mll gene was originally identified through its role in infant acute myeloid and lymphoid leukaemias. Mll also has a role in normal haematopoiesis as identified using mouse knockout models. Homozygous mutation of Mll is embryonic lethal, which has limited research into its role in haematopoiesis. To overcome this embryonic lethality, a conditional knockout mouse model of Mll was established. In this model, exons 9 and 10 of Mll were flanked by LoxP sites ('floxed'), which recombined to induce deletion of exons 9 and 10 in the presence of the Cre recombinase. Deletion of exons 9 and 10 lead to complete loss of the MLL protein as detected by immunoblotting. By breeding mice homozygous for the floxed Mll allele to mice that carried the Cre recombinase under the control of the Vav promoter, it was possible to delete Mll within the haematopoietic system. Analysis of foetal and adult haematopoiesis in the absence of Mll was carried out using the new model. In embryos lacking Mll, the foetal liver showed a marked reduction in the number of colony forming cells as well as both long and short term haematopoietic stem cells. When transplanted into lethally irradiated recipients with wild type competitors, Mll deficient foetal liver cells were unable to contribute to reconstitution of the haematopoietic system. In adult mice, removal of Mll had no apparent effect on the steady state haematopoietic system. Populations of myeloid, lymphoid and stem cells were unaffected. However, in competitive repopulation assays, Mll deficient bone marrow cells were unable to compete with wild type cells. This work suggests Mll is needed for the correct development of foetal liver haematopoiesis and also to maintain self-renewal potential in adult haematopoietic stem cells. However, it appears that Mll is not needed to maintain adult haematopoiesis under homeostatic conditions.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available