About the Project
Background
Lifelong haematopoiesis critically depends on self-renewing haematopoietic stem cells (HSCs) that replenish progenitor cells and give rise to all blood lineages. Acute myeloid leukaemia (AML) is a clonal disorder of HSCs and progenitor cells, which acquire mutations and form treatment-resistant leukaemic stem cells (LSCs) that propagate the disease. Since current therapies often fail to fully eradicate LSCs, leading to high relapse rates in patients, it is essential to understand how LSCs are generated, sustained, and to identify new therapeutic targets for LSC elimination.
Recent evidence indicated that normal and malignant haematopoiesis occur under hypoxic conditions of the bone marrow. As such, we investigated the role of hypoxia-inducible factor- 1alpha (Hif-1alpha) and Hif-2alpha, the main mediators of cellular responses to hypoxia, in these processes. We found that while HSCs do not require Hif- 1alpha and Hif-2alpha to self-renew and sustain haematopoiesis, Hif-1alpha and Hif-2alpha synergise to suppress development and maintenance of LSCs. Our novel findings open up fundamental questions surrounding the molecular mechanisms through which Hifs function as tumour suppressors and the clinical significance of our discovery in AML.
Aims
The central aim of this multidisciplinary project is to address a fundamental question: how do Hifs suppress LSC generation and propagation, and does the level of Hif-dependent signaling determine the clinical outcome of disease in different subtypes of AML? We intend to focus on the following specific aims:
To employ cutting edge genomics (single cell RNA-seq, ATAC-seq and ChIP-seq) and metabolomics coupled with bioinformatics approaches to reveal molecular mechanisms through which Hifs suppress LSC functions;
To use state-of-the-art in vivo approaches to functionally validate the identified pathways that cause aggressive AML upon Hif-1/2alpha deletion;
To employ computational biology approaches to integrate of our datasets with publically available vast resource of human genomic datasets obtained from AML patients to uncover whether and how the Hif system determines the disease severity, drug resistance and prognosis in different subtypes of AML with diverse clinical outcomes.
Finally, bearing in mind that the haematopoietic system serves as a paradigm for our understanding of cellular hierarchies in many other cancers, we will seek to explore the broad ramifications of our findings in stratified medicine.
Training Outcomes
This project will provide the PhD student with multidisciplinary research training at the interface between experimental cancer and stem cell biology, with integral aspects of molecular pathology, genomics, metabolomics and computational genomics.
The student will obtain training in gene knockout strategies, in vivo cancer biology approaches, flow-cytometry analyses and cell sorting, high-content/high-throughput imaging, molecular pathology (including genomic profiling) and cancer metabolism. The student will learn how to generate and apply a diverse range of ‘omics’ data resources (including RNA-seq, ChIP-seq and ATAC-seq datasets) and integrate them to address fundamental questions in molecular pathology, and precision medicine.
The supervisors, Prof. Kamil R Kranc (Edinburgh), Prof. Owen Samson (Glasgow), Dr Vignir Helgason (Glasgow) and Dr Simon Tomlinson (Edinburgh) have expertise and strong track- record in molecular pathology/stem cell biology, cancer/leukaemia metabolism and computational genomics. This unique collaboration will ensure that the student will acquire experimental, quantitative and interdisciplinary skills applicable to many aspects of stratified medicine.
This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.
All applications should be made via the University of Edinburgh, irrespective of project location:
http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919
Please note you must apply to one of the projects and you are encouraged to contact the primary supervisor prior to making your application. Additional information on the application process if available from the link above.
For more information about Precision Medicine visit:
http://www.ed.ac.uk/usher/precision-medicine
References
1. Vukovic, M., Guitart, A., Sepulveda, C., Villacreces, A., O'Duibhir, E., Panagopoulou, T., Ivens, A., Menendez-Gonzalez, J., Iglesias, J.M., Allen, L., Glykofrydis, F., Subramani, C., Armesilla- Diaz, A., Post, A., Schaak, K., Gezer, D., So, C.W.E., Holyoake, T., Wood, A., O'Carroll, D., Ratcliffe, P. & Kranc, K.R. Hif-1α and Hif-2α synergise to suppress AML development but are dispensable for disease maintenance. J. Exp. Med. 212, 2223-2234 (2015).
2. Vukovic, M., Sepulveda, C., Subramani, C., Guitart, A., Mohr, J., Allen, L., Panagopoulou, T., Paris, J., Lawson, H., Villacreces, A., Armesilla-Diaz, A., Gezer, D., Holyoake, T.L., Ratcliffe, P. & Kranc, K.R. Adult haematopoietic stem cells lacking Hif-1α self-renew normally. Blood 127(23), 2841-6 (2016).
3. Guitart, A.V., Subramani, C., Armesilla-Diaz, A., Smith G, Sepulveda, C., Gezer, D., Vukovic, M., Dunn, K., Pollard, P., Holyoake, T.L., Enver, T., Ratcliffe, P.J. & Kranc, K.R. Hif-2alpha is not essential for cell-autonomous hematopoietic stem cell maintenance. Blood 122(10), 1741- 5 (2013).
4.Guitart, A.V., Panagopoulou, T.I., Villacreces, A., Vukovic, M., Sepulveda, C., Allen, L., Carter, R.N., van de Lagemaat, L. N., Morgan, M., Giles, P., Sas, Z., Vila Gonzalez, M., Lawson, H., Paris, J., Edwards-Hicks, J., Schaak, K., Subramani, C., Gezer, D., Armesilla-Diaz, A., Wills, J.C., Easterbrook, A., Coman, D., O’Carroll, D., Vernimmen, D., Rodrigues, N.P., Pollard, P.J., Morton, N.M., Finch. A. & Kranc, K.R. Fumarate hydratase is a critical metabolic regulator of haematopoietic stem cell functions. J. Exp. Med. (2017), Published ahead of print (DOI: 10.1084/jem.20161087).
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