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An investigation into the role of Mll in murine haematopoiesis.

McMahon, K.A.; (2007) An investigation into the role of Mll in murine haematopoiesis. Doctoral thesis , University of London. Green open access

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Abstract

The Mil gene was originally identified through its role in infant acute myeloid and lymphoid leukaemias. Mil also has a role in normal haematopoiesis as identified using mouse knockout models. Homozygous mutation of Mil is embryonic lethal, which has limited research into its role in haematopoiesis. To overcome this embryonic lethality, a conditional knockout mouse model of Mil was established. In this model, exons 9 and 10 of Mil 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 Mil allele to mice that carried the Cre recombinase under the control of the Vav promoter, it was possible to delete Mil within the haematopoietic system. Analysis of foetal and adult haematopoiesis in the absence of Mil was carried out using the new model. In embryos lacking Mil, 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, Mil deficient foetal liver cells were unable to contribute to reconstitution of the haematopoietic system. In adult mice, removal of Mil had no apparent effect on the steady state haematopoietic system. Populations of myeloid, lymphoid and stem cells were unaffected. However, in competitive repopulation assays, Mil deficient bone marrow cells were unable to compete with wild type cells. This work suggests Mil 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 Mil is not needed to maintain adult haematopoiesis under homeostatic conditions.

Type: Thesis (Doctoral)
Title: An investigation into the role of Mll in murine haematopoiesis.
Identifier: PQ ETD:592132
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest
UCL classification:
URI: https://discovery.ucl.ac.uk/id/eprint/1444822
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