The function of PRC2 in MLL-AF4 acute lymphoid leukaemia

Thesis

The MLL-AF4 fusion protein is the most prevalent MLL rearrangement in acute lymphoid leukaemia. It is associated with a very poor prognosis with median overall survival of 10 months in children. Epigenetic therapy is a promising new approach for the treatment haematological malignancies. Predicting response to epigenetic therapy has been difficult, in part due to the lack of sufficient knowledge regarding the molecular mechanism by which these inhibitors exert their anti-leukaemic effects. In this study, inhibition of the PRC2 complex by the EZH2/EZH1 specific small molecule inhibitor UNC1999 in an MLL-AF4 cell line, resulted in a potent anti-leukaemic effect in vitro. Quantitative ChIP-seq (ChIP-Rx) revealed a dose-dependent decrease in H3K27me3 levels following UNC1999 treatment of an MLL-AF4 leukaemic cell line, which was accompanied by a dose-dependent increase in gene expression. A combination of ATACseq, ChIPseq, and Nascent-RNAseq identified a signature of PRC2 target genes that are susceptible to upregulation following inhibition of PRC2; these were genes that were marked by H3K4me3, bound by both RING1B and PRC2 and were expressed at low levels. Knowledge of a signature of genes responsive to PRC2 inhibition may help in predicting responses to epigenetic therapies, which target this complex.

Authors: Tapia, M

• DOI: 10.5287/ora-pvyemxorv
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford