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PhD in Cancer & Genetics - Investigating the influence of Wnt signalling in the leukaemic microenvironment during allogeneic stem cell transplantation


Project Description

AML is an aggressive blood cancer requiring allogeneic stem cell transplantation to improve outcome in the vast majority of poor risk patients. Despite this, at least 40% of transplanted patients suffer a relapse within a year and once leukaemia cells are detectable in the patient’s bone marrow (BM), it is extremely difficult to control the disease as the rapid growth rate of acute leukaemia (AML) coupled with resistance to drug treatment severely reduces the number of patients who can be helped at this stage.
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The bone marrow microenvironment (BMM) is critical in supporting dynamic crosstalk between bone marrow stromal cells (MSCs) and residual leukemic or engrafted donor cells and current research suggests a malignant microenvironment into which the transplanted normal donor stem cells migrate may be unable to support normal cell growth and this may have a significant impact on the re-emergence of the patient’s leukaemia. Drug development to date has focused on clearing the bulk of leukaemic cells and how to target the ‘Leukaemic stem cell,’ which may give rise to relapse. However little work has been undertaken to discover the mechanisms by which the bone marrow microenvironment and the supporting stromal cells communicate and preferentially protect leukaemic cells creating a hostile niche. As relapse following donor grafts is poorly understood and clinicians have little guidance as to which patients will relapse, further research into this area is urgently needed.

Developmental signaling pathways such as Wnt/notch signaling have been implicated in the dysfunctional bone marrow niche, with key roles in suppressing the immune system and stem cell migration associated with AML compared to normal haematopoietic stem cells. The aim of this study is to investigate the contribution of Wnt/beta catenin signalling pathways to the function of the microenvironment in post-transplant AML through the use of serial patient bone marrow samples and novel 2D, 3D microenvironment culture models to identify changes in Wnt signals associated with relapse. We will study the mechanisms by which normal and leukaemic cells could be manipulated to develop drug and cellular treatments that modulate Wnt/β-catenin pathways that can prime the patients microenvironment in favour of normal haematopoietic cell growth and promote immune responses against residual leukaemia cells to improve the outcome of transplants for AML patients.

This PhD project offers the chance to explore novel aspects of the cancer microenvironment and progress our current understanding on the bone marrow niche and immune cell modulation which is an important area of study post-transplant but is as yet poorly studied in AML.

Funding Notes

The studentship is generously funded by the School of Medicine
Full UK/EU tuition fees
Doctoral stipend matching UK Research Council National Minimum
Additional funding is available over the course of the programme and will cover costs such as research consumables and training.
Applicants should possess a minimum of an upper second class Honours degree, master's degree, or equivalent in a relevant subject.
Applicants whose first language is not English are normally expected to meet the minimum University requirements (e.g. 6.5 IELTS)

References

In order to be considered you must submit a formal application via Cardiff University’s online application service. (To access the system click 'Apply Online' at the bottom of this advert)
There is a box at the top right of the page labelled ‘Apply’, please ensure you select the correct ‘Qualification’ (Doctor of Philosophy), the correct ‘Mode of Study’ (Full Time) and the correct ‘Start Date’ (October 2019). This will take you to the application portal.
Candidates are only permitted to submit one application but may select a maximum of three projects, ranked in order of preference in the ‘Research Proposal’ section of the application. In order to be considered candidates must submit the following information:

• Supporting statement
• CV
• Qualification certificates
• References x 2
• Proof of English language (if applicable)

Related Subjects

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