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Regulation of flt3 gene expression in haematopoietic and leukaemic stem cells

Volpe, Giacomo (2010)
Ph.D. thesis, University of Birmingham.

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Abstract

The interaction between the tyrosine kinase receptor Flt3 and its ligand leads to signalling during the commitment of haematopoietic stem cells (HSCs). Constitutive activation of the Flt3/FL pathway is a key factor in enhanced survival and expansion in acute myeloid leukaemia (AML). Although there is extensive knowledge regarding mutations leading to the constitutive activation of Flt3 receptor activity, the molecular mechanisms underlying the regulation of the \(flt3\) gene in HSCs, and how such mechanisms might be altered in leukaemia, are still poorly understood. Here, by using HSC and leukaemic cell lines, I locate several regulatory elements in the \(flt3\) locus by DNaseI mapping and have characterized their epigenetic environment. Analysis of the methylation and acetylation status of histones H3 and H4 around \(flt3 cis\)-regulatory regions highlights a distinct combination of epigenetic modifications specific to AML cells in a region that distinguishes the Flt3\(^-\) and Flt3\(^+\) stages of HSC differentiation. Moreover, I show the link between the \(in vivo\) binding of C/EBP and c-Myb on regulatory elements and epigenetic remodelling in the differential regulation of \(flt3\) in leukaemic cells. Finally, I identify the histone modifiers TIP60 and CBP as potential mediators of the epigenetic regulation of \(flt3\) in AML cells.

Type of Work:Ph.D. thesis.
Supervisor(s):Dumon, Steph
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Immunity and Infection
Subjects:R Medicine (General)
QR180 Immunology
Institution:University of Birmingham
ID Code:822
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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