The function of PRC2 in MLL-AF4 acute lymphoid leukaemia

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. </p

The function of PRC2 in MLL-AF4 acute lymphoid leukaemia

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. </p

H3K9 dimethylation safeguards cancer cells against activation of the interferon pathway

Activation of interferon genes constitutes an important anticancer pathway able to restrict proliferation of cancer cells. Here, we demonstrate that the H3K9me3 histone methyltransferase (HMT) suppressor of variegation 3–9 homolog 1 (SUV39H1) is required for the proliferation of acute myeloid leukemia (AML) and find that its loss leads to activation of the interferon pathway. Mechanistically, we show that this occurs via destabilization of a complex composed of SUV39H1 and the two H3K9me2 HMTs, G9A and GLP. Indeed, loss of H3K9me2 correlated with the activation of key interferon pathway genes, and interference with the activities of G9A/GLP largely phenocopied loss of SUV39H1. Last, we demonstrate that inhibition of G9A/GLP synergized with DNA demethylating agents and that SUV39H1 constitutes a potential biomarker for the response to hypomethylation treatment. Collectively, we uncovered a clinically relevant role for H3K9me2 in safeguarding cancer cells against activation of the interferon pathway