The role of RNA modifications in myeloid leukaemogenesis (360G-Wellcome-210926_Z_18_Z)

Acute myeloid leukaemia (AML) is a devastating cancer with a long-term survival below 30% for which mainstream treatments remain unchanged for several decades. Advances in genomics have highlighted the importance of epigenetic corruption in both initiating and maintaining the disease, making the epigenome an important therapeutic focus. Recently, using CRISPR-Cas9 recessive genetic screens, we identified several RNA-binding/modifying proteins as essential for AML cell survival. We have since confirmed that the RNA methyltransferase METTL3 is required for AML maintenance through its role in co-transcriptional N6 adenosine methylation of target RNAs, but is dispensable for normal haematopoiesis proposing it as a novel "druggable" therapeutic target in AML (Barbieri, Tzelepis et al, Nature 2017). Here, I propose to extend the investigation of the epitranscriptome as a new therapeutic focus in AML by studying promising AML-essential RNA-binding/modifying proteins, including METTL1 and METTL16, using unique reagents and expertise as well as access to clinically relevant bespoke models and human samples.