The role of the mixed lineage leukaemia gene in haematopoiesis and leukaemogenesis
File(s)
Author(s)
Meng, Yiran
Type
Thesis
Abstract
Mixed lineage leukaemia (MLL) is an evolutionarily conserved gene expressing a protein with histone methyltransferase activity. It was firstly identified by its role in leukaemia. MLL fusion proteins generated by chromosomal translocations are detected in over 70% of acute infant leukaemias. The mechanism by which MLL fusions induce leukaemia remains in question. Two separate theories propose that MLL fusions act either in a gain-of-function or in an MLL-dependent manner. MLL also has a role in normal haematopoiesis. In a conditional knockout mouse model where both Mll alleles are only deleted within the haematopoietic system, Mll-deficient bone marrow has impaired long-term repopulating ability. Therefore, Mll is proposed to be essential to the self-renewal ability of haematopoietic stem cells (HSCs). The studies presented here describe the development of a novel in vitro assay to rapidly screen for the effects of individual genes on HSC function. A subset of Hox genes are found to be the potential downstream targets of Mll in the control of HSC self-renewal. The work has also demonstrated that WT Mll is dispensable for the MLL-fusion-induced immortalisation of haematopoietic progenitors. This finding suggests that MLL fusion proteins have a dominant effect on the immortalisation of haematopoietic cells and that this is independent of the expression of WT Mll.
Version
Open Access
Date Issued
2016-03
Date Awarded
2017-02
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Brady, Hugh
Publisher Department
Life Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)