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Investigating the impact of commonly occurring blood cancer mutations on innate immune signalling

School of Medicine, Dentistry and Biomedical Sciences | PHD

Applications are now CLOSED
Funding
Funded
Reference Number
SMED-2251-1002
Application Deadline
28 November 2024
Start Date
1 October 2025

Overview

Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) are clonal haematological malignancies that can disrupt normal haematopoiesis of multiple myeloid lineages. MDS/AML are frequently diagnosed in the older population (onset ~65 years). They are characterised by molecular and/or cytogenetic abnormalities accompanied by peripheral blood cytopenias. Due to the age group affected, treatment can be difficult due to the fitness of the patient and the toxicity associated with therapies currently used. The successes of graft-vs-leukaemia observed following allogeneic hematopoietic stem cell transplant (HSCT) supports the value immunotherapy could have for MDS and AML patients. It has previously been reported that DNA damage response deficiencies (DDRD), result in the activation of the cGAS/STING-dependent innate immune response through cytosolic DNA sensing, thereby linking DDRD with modulation of the adaptive immune response. More biological pathways mediating immune activation in cancer are becoming apparent. This study will identify some of these pathways in a myeloid malignancy setting and explore the value of using targeted-drugs in combination with immunotherapies for the treatment of MDS/AML. The purpose of this research is to explore immune activation in myeloid malignancies, investigating the role of commonly occurring mutations in immune signalling in a blood cancer setting.

This study has three work-packages, the first of which will be validation of the role of mutant FLT3, IDH2 and EZH2 in immune evasion. The second work-package will focus on identifying further immune evasion pathways involved in the pathogenesis of MDS/AML using a larger scale esiRNA screen. This screen will target pathways involved in MDS/AML development and progression, including pathways important for the maintenance of leukaemic stem cells. And work-package 3 will take the findings from WP1/2 and use the chorioallantoic membrane model to validate the findings in an immune competent in vivo model.

The successful applicant will use esiRNA screening to investigate the impact of the loss of commonly mutated genes in MDS/AML using an immune cytokine ELISA as a readout. The student will also employ CRISPR editing techniques to knock-in MDS/AML specific mutations of those genes that can influence innate immune signalling with loss. Additionally, the successful applicant will use many molecular biology techniques including Western blotting, PCR, immunofluorescence, flow cytometry, etc. It is hoped that disease specific mutations able to promote innate immune signalling will be targetable with immune checkpoint blockade (ICB) therapies and/or developing ICB combination therapies in the patient setting.

Funding Information

Funded by the Department for the Economy (DfE). For UK domiciled students the value of an award includes the cost of approved tuition fees and maintenance support the 2025/26 rates are still to be confirmed (current rates for 2024/25 are Fees £4,786, Stipend £19,237).  To be considered eligible you must have been ordinarily resident in the UK for the full 3-year period prior to the start of the studentship and you must be ordinarily resident in Northern Ireland on the first day of the start of the studentship.  For further information about eligibility criteria please refer to the DfE Postgraduate Studentship Terms and Conditions at https://www.economy-ni.gov.uk/publications/student-finance-postgraduate-studentships-terms-and-conditions

Project Summary
Supervisor

Dr Katrina Lappin

Research Profile


Mode of Study

Full-time: 3 Years


Funding Body
DfE
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