Functional dissection of myelodysplastic syndrome disease progression

Project Outline

Blood cancer often results from mutations in genes controlling normal stem cell development. Blood cancers derived from bone marrow provide a good model to study this process. Myelodysplastic syndrome (MDS) results from an accumulation of 4 genetic mutations in haematopoietic stem cells (HSCs) that allow them to out-compete healthy HSCs. During progression of MDS, one clone ultimately outcompetes others resulting in bone marrow failure and/or acute myeloid leukaemia (AML), both life threatening, outcomes.

Understanding how myelodysplastic HSCs outcompete healthy ones will allow us to design new treatments to prevent this from happening and inform monitoring strategies during disease evolution. Prior attempts to model the mutational complexity seen in human MDS clones have been limited by technical issues. We have developed a new transgenic mouse expressing a CRISPR enzyme that allows multiple, bespoke genetic edits in each HSC. We will then characterise these mutated HSCs to understand what effect they have on normal blood development. It is unclear whether specific combination of mutations together influence treatment outcomes: therefore, our second goal is to understand whether there are treatments that are dependent on these mutations interacting together.

You will benefit from training in a broad range of laboratory-based techniques ranging from molecular biology to animal work. In addition to an outstanding scientific training, you will have the opportunity for broad exposure to the clinical activity of The Christie Haematology Department which provides standard-of-care, and clinical trials. You will also benefit from integration into a highly translational environment including the use of primary patient samples to validate and inform the mechanistic studies. You will become an expert in the molecular genetics of myeloid disease, which is now fundamental to care for our patients. Finally, your experience will enable you to develop your own independent enquiries going forward.

Applications for this project are now open. Please complete your application on The University of Manchester website.