FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia

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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.