The therapeutic targeting of epitranscriptome-associated proteins
Konstantinos Tzelepis
Cambridge Stem Cell Institute, University of Cambridge
Epitranscriptomics, the modulation of RNA function via its chemical modification, has emerged as a pervasive new mechanism of gene regulation. The role of the epitranscriptome on stem cell fate, maintenance and ageing remains largely unexplored. Similarly, the impact of aberrant RNA modification and editing on oncogenic transformation and cancer stem cell maintenance remains poorly investigated, however early studies suggest that the modification of RNA could be exploited for the development of new therapies for devastating diseases including anti-leukaemia therapies. The Tzelepis group investigates the relevance of RNA modifications in normal and malignant stem cell biology. Using sophisticated functional screening platforms, the lab has identified a significant number of epitranscriptomic vulnerabilities of acute myeloid leukaemia (AML) and have gone on to investigate some of these in detail, including the m6A writer METTL3 (Barbieri et al, Nature, 2017) and the m7G writer METTL1 (Orellana et al, Molecular Cell, 2021). Notably, their latest studies reporting the first-in-class METTL3 inhibitor (Yankova et al, Nature, 2021) (Sturgess et al, Leukemia, 2023) and the discovery of cancer-biased cell surface RBPs (George et al, Nature Biotechnology, 2025) provide strong proof-of-concept that epitranscriptome-associated proteins represent a new promising avenue for therapeutic development. Recently, his group co-developed and characterised a range of pre-clinical and clinical epitranscriptomic modalities. Future aims include study of selected RNA modifying enzymes and cell surface RBPs which we have identified as essential for either normal or malignant stem cells and whose function is currently unknown or incompletely understood with a particular focus on how particular RNA modifications regulate cell fate, differentiation, ageing and carcinogenesis.