Cancer epigenetics: From mechanism to therapy


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Mark Dawson1
1Cambridge Institute for Medical Research & Wellcome Trust and Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK

Abstract

Chemical modifications of histones and DNA occurs through highly conserved enzymes, and these modifications are in turn 'read' by chromatin adaptor proteins. The information conveyed by these processes plays a critical role in the regulation of all DNA based processes such as transcription, DNA repair and replication. Consequently, when these epigenetic enzymes or readers are mutated the results are often devastating and lead to the induction and/or maintenance of various cancers. Understanding the molecular mechanisms by which these epigenetic regulators contribute to cancer may provide an opportunity to target these factors with novel epigenetic therapies. We have recently identified a previously unrecognised nuclear role for JAK2 as a histone tyrosine kinase and demonstrated a novel signalling pathway by which JAK2 directly regulates chromatin structure and transcription in mammalian cells (Dawson et al; Nature 2009). Our current research has centred on deciphering the molecular mechanisms by which MLL-fusions regulate transcriptional programmes involved in leukaemogenesis. We have identified the BET proteins, in particular BRD4, as components of large macromolecular chromatin complexes associated with MLL-fusions and have demonstrated that small molecules that target these epigenetic readers are effective therapeutic agents in MLL-fusion leukaemia (Dawson et al; Nature 2011).