About the Project
Acute myeloid leukaemia (AML) is a cancer of the bone marrow (BM) microenvironment. Presently approximately 80% of patients diagnosed with AML will die of the disease, most within a year of diagnosis. Our group has recently defined novel pro-tumoral interactions between leukaemia cells and the non-malignant microenvironment cells that surround them which promote AML survival, proliferation and chemotherapy resistance. In this research project we hypothesise that the BM microenvironment of AML changes from a ‘non-diseased’ BM phenotype to a definable pro-tumoural ‘diseased’ BM phenotype. Moreover we propose that this phenotypic change within the non-malignant cells of the bone marrow is driven by the leukaemia and furthermore necessary for tumour survival. The detail of these changes are presently unknown. In addition it is also unknown at what stage of AML disease development do the BM microenvironment changes begin to occur and in which order.
Therefore this project aims to use an in-vivo model of AML (already established in our lab (all necessary ethical and home office permissions in place) in which samples of primary AML taken from patients attending the Norfolk and Norwich University Hospital will be transplanted into immunocompromised NSG mice. We will then harvest the tissue from the BM of engrafted diseased animals at different time points post transplantation and then single cell sort the mesenchymal cells for single cell transcriptome analysis. It is envisaged that information generated from this descriptive research (phase 1 – years 1 and 2) will immediately lead to further hypothesis driven studies for the studentship investigating the essential components of the bi-directional crosstalk between AML and the cells in the surrounding micro-environment (phase 2 – years 2 and 3). Further forward and more broadly we expect the data generated from this work will define new therapeutic targets to treat AML.
For more information on the supervisor of this project, please go here: https://www.uea.ac.uk/medicine/people/profile/s-rushworth
Type of programme: PhD
Start Date: Jan 2018
Mode of study: Full-time
Entry requirements
Acceptable first degrees are not limited to but include: Biological Sciences, Biomedical Sciences, Natural Sciences, Biochemistry, Bioinformatics, Bio-engineering
The standard minimum entry requirement is 2:1 or above or a Masters degree.
Funding Notes
This PhD project is jointly funded by the Faculty of Medicine and Health Sciencesand the Earlham Institute funded studentship. This studentship is funded for 3 years and comprises home/EU fees, an annual stipend of £14,057 and £1000 per annum to support research training.
References
i) 1] Shafat MS, Gnaneswaran B, Bowles KM, Rushworth SA. The bone marrow microenvironment - Home of the leukemic blasts. Blood Reviews. 2017 Mar 12. pii: S0268-960X(16)30073-X. doi: 10.1016/j.blre.2017.03.004. [Epub ahead of print]
ii) Shafat MS, Oellerich T, Mohr S, Robinson SD, Edwards DR, Marlein CR, Piddock RE, Fenech M, Zaitseva L, Abdul-Aziz A, Turner J, Watkins JA, Lawes M, Bowles KM, Rushworth SA. Leukemic blasts program bone marrow adipocytes to generate a protumoral microenvironment. Blood. 2017 Mar 9;129(10):1320-1332.
iii) Abdul-Aziz AM, Shafat MS, Mehta TK, Di Palma F, Lawes MJ, Rushworth SA, Bowles KM.
MIF-Induced Stromal PKCβ/IL8 Is Essential in Human Acute Myeloid Leukemia. Cancer Research. 2017 Jan 15;77(2):303-311.
iv) Pillinger G, Loughran NV, Piddock RE, Shafat MS, Zaitseva L, Abdul-Aziz A, Lawes MJ, Bowles KM, Rushworth SA. Targeting PI3Kδ and PI3Kγ signalling disrupts human AML survival and bone marrow stromal cell mediated protection. Oncotarget. 2016 Jun 28;7(26):39784-39795.
v) Marlein C, Zaitseva L, Piddock RE, Robinson S, Edwards DR, Shafat MS, Bowles KM, Rushworth SA. Bone Marrow Mesenchymal Stromal Cells Transfer Their Mitochondria to Acute Myeloid Leukaemia Blasts to Support Their Proliferation and Survival. Blood 2016 128:772.
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