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Multi-level mass cytometric analysis of transcription factor mutations in driving human leukaemia sensitivity

Project Description

Myelodysplastic syndrome (MDS) is a blood disorder with morphological dysplasia and ineffective haematopoiesis leading to cytopenias. It is a pre-leukemic condition which transforms to acute myeloid leukaemia (AML) in 30% of all cases, and is increasingly common in the elderly (median age 66 years). Prognosis for either MDS or AML is poor as clinicians are presently devoid of good drug treatments. Multi-parameter flow cytometry improves diagnostic and prognostic accuracy in MDS patients, but is limited as only a limited number of parameters can be measured per cell. Although flow cytometers are purported to measure up to 21 fluorochromes per cell, in practice this is technically challenging and 3- to 10-colour flow panels are more typical. Here we will use a more novel mass cytometry (CyTOF) expertise to understand MDS to AML progression. This superior technology utilises ‘heavy metal tagged probes’ to allow greater multiplexing of typically >45 parameters per cell. We have recently optimised and incorporated ‘the proximity ligation assay for RNA’ (PLAYR) into mass cytometry technique for simultaneous detection of RNA and antigens (surface and intracellular). We have proven this technology in our labs analysing normal peripheral blood mononuclear cells (PBMCs) and primary cells from chronic leukaemia patients. Through our Merseyside & Cheshire regional Haemato-oncology diagnostic service we will analyse ethically-approved serial primary blood and bone marrow samples from indolent and transformed MDS and AML patients. Using CyTOF and PLAYR techniques, we will provide additional information on B-, T-, and NK- lymphocytes within patient samples, which may also influence disease progression and drug-sensitivity in MDS and AML patients. We hypothesise that the evaluation of an expanded panel of critical myeloid transcriptional factors and pathways (e.g. RUNX, GATA, TGF-β) by combined PLAYR and mass cytometry will allow greater understanding of patient intraclonal heterogeneity and help better our understanding of this disease biology and behaviour. These studies will help train a future leading scientist in the field of Haemato-oncology and Pharmacology, providing them with cutting-edge expertise and better understanding of the clinical problems and issues to be tackled, for the betterment of patients.

The aim of this project is to explore better phenotypic and genotypic characterisation of primary cells from MDS patients using CyTOF and PLAYR technology with a focus on intraclonal heterogeneity. The specific objectives of the proposed studies are: (i) To build on the EuroFlow 6 and European Leukemia Net criteria for MDS to develop an expanded immunophenotyping panel for mass cytometry that will allow examination of clonal and normal hematopoietic cells in patient-derived PB and BM samples, (ii) To develop a PLAYR panel of relevant RNAs (to be studied alongside proteins), for mass cytometric evaluation. Specific genetic aberrations that predicate disease progression of MDS to AML will be targeted for evaluation 2, (iii) To benchmark the performance of the combined CyTOF/PLAYR panel against standard diagnostic and monitoring techniques (i.e. Morphology, Flow cytometry and Cytogenetics) in serial MDS samples to predict disease behaviour and therapy outcomes.

To apply please send your CV, cover letter and the names and addresses of two references to .
For application enquires please contact Professor David MacEwan ()

Applicants will have a first class or upper second class honours degree (or equivalent) in the biological sciences and some laboratory research experience. You may have additional masters level research experience in cell biology, biochemistry or cancer research. All applicants must satisfy the appropriate University English language requirements. For EU and international students this is an IELTS score of 6.5 with no band score lower than 5.5.

Funding Notes

This 3-year PhD studentship covers tuition fees, research support costs and a stipend at UKRI standard rates (£14,999 p.a. for 2019/20). The studentship is open to UK, EU and international candidates

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