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Title: Genome-wide analyses reveal new insights into MLL fusion protein recruitment mechanisms
Author: Kerry, Jonathan
ISNI:       0000 0004 6346 7644
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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Leukaemias arising from rearrangements of the MLL1 gene are responsible for the majority of infant leukaemias as well as a proportion of childhood and adult leukaemias. The aggressive nature and resistance to therapy of these leukaemias has made them the focus of many therapeutic studies. Targeted therapies for MLL-rearranged (MLL-r) leukaemias are starting to enter clinical trials in an attempt to improve on outcomes from more standard treatments such as chemotherapy. MLL fusion proteins (MLL-FPs) are recruited to gene targets where they cause aberrant upregulation of gene expression, leading to leukaemia development. Therefore, targeting the recruitment of MLL-FPs to gene targets presents one possibility for a therapeutic strategy. Before this can be achieved a thorough understanding of MLL-FP recruitment is required. Data presented in this thesis tests some of the current models of MLL-FP recruitment on a genome-wide level. This study shows that the Menin/LEDGF complex is a good candidate for global MLL-FP recruitment to gene targets. However, data here shows that MLL-FPs can also recruit Menin, suggesting that models up to this point have been incomplete with regards to the Menin-MLL-FP interaction. It is shown here that the PAF elongation complex is unable to recruit MLL-FPs unlike previously thought. Investigation into genes marked by broad, or 'spreading', domains of MLL-FP recruitment shows that these genes have increased expression and correlate with poor survival outcomes in MLL-r leukaemia patients. Analysis of the mechanism behind MLL-FP spreading recruitment implicates the Menin/LEDGF and super elongation complex as important for this process.
Supervisor: Milne, Thomas Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available