Understanding the role of RNA modifications in myeloid leukaemogenesis

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 and maintenance remains largely unexplored. Similarly, the role 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 devastated diseases including cancer. Our lab has a track record in the discovery and mechanistic characterisation of enzymes that modify RNA as well as the development and characterisation of small molecule inhibitors targeting such enzymes in cancer. Here, I propose to expand my investigations in order to study how particular RNA modifications regulate cell fate, differentiation and oncogenesis in the context of normal and malignant haematopoiesis. I expect the outcomes of this proposal will: (a) lead to currently unknown or incompletely understood fundamental RNA biology, (b) provide a strong mechanistic and functional understanding for the disease-associated role of selected RNA-modifying enzymes and (c) define new druggable epitranscriptomic pathways in leukaemia and beyond.