Transposable elements as a source of novel isoforms and immunotherapy targets in Paediatric Acute Myeloid Leukaemia

Primary supervisor: Özgen Deniz, Queen Mary University of London

Secondary supervisor: Richard Dillon, King’s College London

Project

Project background and description:

Paediatric acute myeloid leukaemia (pAML) is a highly heterogeneous disease, accounting for ~15-20% of all childhood leukaemia cases. Despite advances in diagnosis and treatment, pAML remains life-threatening, with an overall survival rate of ~65% [1]. Thus, there is an urgent need for novel treatments that are specific with durable benefits.

Transposable elements (TEs) constitute nearly half of the human genome and are normally silenced by epigenetic mechanisms [2]. However, in cancer, epigenetic dysregulation can reactivate TEs, which can initiate transcription, prematurely terminate genes, introduce alternative splice sites, or drive transcriptional readthrough. This generates a dynamic repertoire of chimeric transcripts and unannotated protein isoforms with altered domains and function, some of which may encode unique peptides, so-called neoantigens, presented on the tumour cell surface by MHC molecules and recognised by the immune system [3]. Such neoantigens are highly attractive as potential biomarkers and immunotherapy targets, as they are tumour-specific and absent from normal tissues. Yet, the landscape and therapeutic potential of TE-derived transcripts and peptides remain unexplored in pAML.

This PhD project aims to systematically characterise TE-chimeric isoforms and assess their potential as immunotherapeutic targets in pAML. The project will focus on high-risk pAML subgroups: NUP98 fusions, KMT2A rearrangements, and UBTF tandem duplications, and identify mutation-specific TE-derived transcripts within these subgroups to ensure that candidate neoantigens are unique to mutated-malignant cells, thereby minimising the risk of off-target effects. Importantly, this project will leverage the resources of clinical samples and data collected in the international MyeChild01 study, where Dr Richard Dillon is one of the molecular leads. MyeChild01 completed recruitment of >700 children with AML and transcriptomic and genomic profiling have already been performed on these diagnostic samples. The specific aims are:

Aim 1: To identify TE-derived transcripts and fusion events in high-risk pAML subtypes using short-read RNA-seq data from the MyeChild01 and TARGET datasets [4], complemented by long-read RNA sequencing in selected MyeChild01 samples to resolve full-length isoforms and novel open reading frames.

Aim 2: To predict TE-derived peptides with high tumour specificity from these transcripts in silico and experimentally validate their presentation on AML cell surfaces through immunopeptidomics, using HLA class I pulldown and liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Aim 3: To functionally characterise candidate TE-derived isoforms by activating their expression using CRISPR activation or silencing endogenous transcripts using antisense oligonucleotides [5] and evaluate their immunogenicity using T cell activation assays, assessing their potential as immunotherapy targets.

This project offers an innovative and interdisciplinary training experience at the intersection of cancer genomics, immunology, bioinformatics. It will develop and apply new bioinformatic pipelines for transcriptomic analysis, neoantigen prediction, and structural modelling, integrated with experimental validation using immunopeptidomics and CRISPR-based perturbation. By systematically identifying and validating TE-derived neoantigens in high-risk pAML, this work aims to uncover potential targets for future immunotherapies tailored to childhood leukaemia.

Candidate background

We seek highly motivated candidates with a background in cancer genomics, immunology, or bioinformatics, and an interest in transcriptomics and immunotherapy. Experience with RNA-seq analysis, CRISPR technologies, and proteomics is advantageous.

Potential Research Placements

1. Richard Dillon, Department of Medical & Molecular Genetics, King’s College London
2. Mirjana Efremova, Barts Cancer Institute, Queen Mary University of London
3. Luigi Ombrato, Barts Cancer Institute, Queen Mary University of London

References

1. Pui, C.H. et al. (2011) Biology, risk stratification, and therapy of pediatric acute leukemias: An update. J Clin Oncol; 29:551–565.
2. Prokopov, D., Tunbak, H., Leddy, E., Drylie, B., Camera F., Deniz, O (2025) Transposable elements as genome regulators in normal and malignant haematopoiesis. Blood Cancer J. 15, 87 .
3. Shah NM, Jang HJ, Liang Y, et al (2023) Pan-cancer analysis identifies tumor-specific antigens derived from transposable elements. Nat Genet;55(4):631-639. doi:10.1038/s41588-023-01349-3
4. Bolouri, H. et al. (2018) The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions. Nature Medicine; 24, 103–112
5. Kim, J., et al (2019) Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease. NEJM; 381:1644-1652