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Investigation of novel HOX interactors as potential therapeutic targets in leukaemia


About This PhD Project

Project Description

This 4 year PhD studentship offered in Professor Georges Lacaud’s research group is based at the Cancer Research UK Manchester Institute, Alderley Park, Cheshire

Acute myeloid leukaemia (AML) is a clinically and genetically heterogeneous disease with poor prognosis. Treatments for AML have not dramatically changed, or improved, over the last 30 years and there is a pressing need for newer and more efficient therapies.

Translocations involving the epigenetic factors MOZ and MLL result in the creation of novel fusion proteins giving rise to some of the most aggressive AMLs. MOZ and MLL rearranged leukaemias are characterised by high expression of several HOX genes and their co-factors that form part of the Leukaemic Stem Cell (LSC) signature. A similar gene expression profile suggests that these two very aggressive subtypes of AML share molecular pathways that might be critical for leukaemogenesis. From a therapeutic perspective, understanding the dysregulation of these shared signalling cascades may help elucidate differences between LSC and normal Haematopoietic Stem and Progenitor Cell (HSPC) populations for the development of targeted therapies.

To this end, we have identified upregulation in the expression of a core network of genes, some of which are also novel interactors of HOX proteins. These interactions are observed across a range of murine and human leukaemic cell lines, as well as in primary patient samples. The results thus far suggest that these novel interactions potentiate the leukaemogenic capacity of HOX genes and that they are critical factors for the initiation and/or maintenance of MOZ- and MLL-related AMLs, thereby opening up promising therapeutic avenues.

This PhD represents an exciting opportunity for the student to join an advanced project to further elucidate the role of these interactions in the initiation and/or maintenance of MOZ and MLL rearranged AMLs. The project will focus on delineating the mechanisms employed by this network of genes to promote leukaemia using state of the art methods such as single cell RNA Seq, Chromatin immunoprecipitation sequencing, flow cytometry, mass cytometry (CyTOF), mass spectrometry and imaging. The project will also involve employing models, such as patient derived xenograft models, to assess the therapeutic potential of disrupting these protein partnerships.

Applications are invited from exceptionally high calibre students, graduates or final year undergraduates who should hold or are expected to gain a first/upper second-class honours degree in a relevant subject as part of a University degree course.

Applicants can find full group project details, entry criteria and details on how to apply online at:
http://www.cruk.manchester.ac.uk/education/PhD-Studentships

Closing date: Friday 3 January 2020 – 2100 hours GMT

Interview date: Tuesday 18 February 2020, Alderley Park, Cheshire

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