Transcriptional and epigenetic profiling of leukaemia stem cells for precision medicine

Dr Xu Huang (Cancer Sciences, University of Glasgow)
Prof Robert Liskamp (Chemistry, University of Glasgow)
Dr Mark Drummond (Beatson West of Scotland Cancer Centre/NHS)

There is a significant unmet need for novel therapeutic approaches in blood cancer. Current treatment has evolved little since several decades ago especially for Acute Myeloid Leukaemia (AML). The recent development of several pharmacological inhibitors targeting BRD4 and Dot1L, highlights that such epigenetic regulators could be promising antitumour targets. Based on our previous shRNA screen results, we have identified a histone demethylase, depletion of which in human AML cells promoted AML cancer stem cells terminal myeloid differentiation and rapid cell death but spared normal haemopoietic stem cell function. This suggests that this protein could represent rational target for therapeutic intervention. However, it lacks in-depth understanding of the cellular mechanisms through which this demethylase and its inhibitors selectively target leukaemic cancer stem cells. In this project we will focus on identifying its specific downstream targets in AML, and validate the results in primary AML patient samples and in our established human AML xenograft mouse model. The proposed study will utilise combined systems biology approaches and expects to provide a fundamental scientific understanding to be used to initiate the next stage of drug discovery and propose the effective combination treatments with other standard AML therapies.

Keywords: Acute myeloid leukaemia, Epigenetic regulation, Leukaemia stem cell


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