Wellcome Trust PhD Programme for Clinicians at the University of Cambridge. The role of EZH2 in the induction and maintenance of acute myeloid leukaemia. (360G-Wellcome-103393_Z_13_A)

This proposal aims to delineate the role of the epigenetic regulator EZH2, whose function is perturbed in a number of cancers including leukaemia and lymphoma, in the induction and maintenance of acute myeloid leukaemia (AML). AML is an aggressive haematological malignancy with an overall poor outlook and limited treatment options in the relapse setting. We aim to provide genetic proof of the requirement of EZH2 across multiple subtypes of AML, employing both conditional knockout and overexpression approaches both in vitro using immortalised cell lines, and in in vivo experiments in mice. The primarygoal is to demonstrate the role of EZH2 in both the induction and maintenance of AML. Having established this,we will characterise which transcriptional programmes EZH2 alters in the maintenance of AML, utilising RNA-Seq/ChIP-seq analysis of AML cell lines following exposure to a novel EZH2 inhibitor and cells from theconditional knockouts generated in the previous aim. Additionally we aim to further preclinical testing of the efficacy of the EZH2 inhibitor in AML. Combining these three aims with an evaluation of the mechanism for EZH2 activation and any alternative functions of the EZH2 protein in the leukaemic phenotype, our key goal is to provide a robust assessment of the role of EZH2 in AML.