More than half of our DNA is made of mobile genetic fragments called transposable elements, and this project will systematically test whether they actively drive cancer growth or suppress it. These elements have long been dismissed as junk DNA, but scattered examples suggest they can switch genes on or off. No one has yet mapped their collective influence on a living cell. The team will focus on acute myeloid leukaemia, a blood cancer where the genome’s chemical tags go haywire, creating ideal conditions for transposable elements to wake up. By combining genomics, protein analysis, and gene-editing tools, they will identify which elements act as oncogenes, which act as tumour suppressors, and which provoke the immune system to attack the cancer. If successful, the work will transform a vast, neglected portion of the genome from a curiosity into a therapeutic target. Understanding how transposable elements regulate cell behaviour could lead to new drugs that either silence harmful elements or harness immunogenic ones to boost the body’s own anti-cancer response. The project is fundamental science, but it directly addresses a gap that has kept half the human genome clinically invisible.
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Accounting for more than half of the human genome, transposable elements (TEs) provide a rich source of transcriptional modulatory elements and have potential to regulate cellular processes. There are well-established examples of TEs that contribute to transcriptional networks, however these examples are limited and mainly shown in a locus-specific manner. Direct assessment of the biological consequences of TE activities and understanding the extent to which they influence cellular functions remains unexplored. FITEAML will comprehensively characterize the genome-wide contribution of TEs to cellular function and phenotypes in a context that provides a fertile ground for their activity: acute myeloid leukaemia (AML). Widespread epigenetic changes are characteristic features of AML, making AML an ideal model system to test the significance of TE activation on genome function while also offering an excellent opportunity to model the evolutionary co-option of TEs. Focusing on three distinct biological activities of TEs (oncogenic, tumor suppressor and immunogenic) we will combine genomics, bioinformatics, proteomics and molecular techniques to: i) comprehensively identify TE-derived cis-regulatory sequences and determine their implications on transcriptional networks; ii) assess the impact of their targeted manipulation on cellular fitness and phenotype; iii) characterize the roles of TEs in anti-tumor immune responses; and iv) provide novel and detailed mechanistic insights into TE regulation. The outcomes of FITEAML will fill a large gap of knowledge in understanding the functionality of TEs in cellular function and provide fundamental insights into the key question: How do TEs modulate cellular phenotypes and contribute to genome function? In addition to revealing mechanistic links between TEs and host biology, FITEAML will prove how this knowledge could be exploited for clinical medicine and provide a potential therapeutic route in cancer.
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