Project ID CM-HD2023_56

ThemeCM-HD

Co Supervisor 1A School of Immunology & Microbial SciencesWebsite

Co Supervisor 1B Department of Medical and Molecular GeneticsWebsite

Identifying molecular and immunological vulnerabilities of fusion-gene driven acute myeloid leukaemia

Acute myeloid leukaemia (AML) in children remains a significant unmet. Most paediatric AML are characterised by gene fusions associated to clinical prognosis.

This project aims to define the immunogenicity of noncanonical antigenic peptides derived from fusion genes in childhood AML, assess the impact of the fusion genes on the patients’ immunome and clinical response, and to apply unbiassed screening methodologies to identify therapeutic vulnerabilities of gene fusions with particularly poor outcomes in order to design precision targeted combination therapies.

The project objective can be achieved by applying a multi-disciplinary strategy for target discovery that involves in silico, in vitro, ex vivo approaches combined with a clinical framework.

The outcome of the project could pave the way to translational applications such as vaccination and adoptive T cell therapies in childhood AML via immunotherapy within a personalised-medicine framework.

The project will be supported by: (i) Mishto lab (molecular immunology; KCL, UK), Dillon lab (AML; KCL, UK); Liepe lab (Quantitative System Biology; MPI-NAT, D).

The student will investigate:
1. Fusion gene-derived neoepitope candidates presented specifically by AML cells.
2. Techniques: bioinformatics, biochemistry, proteomics.
3. Immunogenicity of AML-specific neoepitopes in childhood AML patients.
4. Techniques: cellular immunology, T-cell FACS and sorting, TCR cloning and transductions, molecular immunology.
5. Association between fusion genes, AML-specific CD8 T cells and response to therapy in childhood AML.
6. Techniques: bioinformatics, statistics.
7. Therapeutic vulnerabilities that could be exploited to synergise with immunotherapeutic approaches.
8. Techniques: CRISPR screening in cell line models, direct drug sensitivity assays in primary patient samples.

One representative publication from each co-supervisor:

• Liepe J, Marino F, Sidney J, Jeko A, Bunting DE, Sette A, Kloetzel PM, Stumpf MP, Heck AJ, Mishto M. A large fraction of HLA class I ligands are proteasome-generated spliced peptides. Science 2016 Oct; 354(6310): 354-358. DOI: 10.1126/science.aaf4384.

• R Dillon, N Potter, S Freeman, N Russell. How we use molecular minimal residual disease (MRD) testing in acute myeloid leukaemia (AML). British Journal of Haematology 2022. 193(2) 231-244.