This project will explore immune activation in myelodysplastic syndrome and acute myeloid leukaemia, investigating how commonly occurring mutations in these blood cancers can, either be, exploited to promote immune activation or promote immune evasion.
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 with a median age of onset >70 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.
The aim of this project is to explore mutations known to cause DDRD in MDS/AML to determine if they can enhance immune activation in these myeloid malignancies.
The successful applicant will generate cell line models using a luciferase dual reporter construct, which links luminescence to PD-L1 transcription, a well characterised marker of innate immune activation, using our CRISPR generated mutant models. Drugs which can activate immune biology in the mutant models will be determined with high-throughput drug screening, assaying luminescence (PD-L1 transcription) at multiple time-points. Successful compounds will be analysed further with RNA-sequencing and cGAS/STING dependency studies will follow.
Eligibility for a full DfE studentship requires you to have been resident in the United Kingdom for a three-year period before the first day of the first academic year of the course. You must hold or expect to gain an upper second-class honours degree.
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