EZH2 upregulates the PI3K/AKT pathway through IGF1R and MYC in clinically aggressive CLL

In this study, using ChIP sequencing, we identified EZH2 target genes in two prognostic subgroups of chronic lymphocytic leukemia with distinct outcome, i.e. IGHV-unmutated/subset #1 and IGHV-mutated/subset #4. Our data identified many oncogenic pathways enriched equally by EZH2 target genes in both prognostic subgroups. Importantly, we identified PI3K pathway as differentially enriched pathway by EZH2 between the two prognostic sub groups. Validation of EZH2 target genes for EZH2 occupancy on selected PI3K pathway target genes were performed using independent CLL patient samples and CLL cell lines using siRNA mediated down regulation and ChIP assays. In conclusion, for the first time we characterized EZH2 target genes in CLL to understand the role of EZH2 in regulating the oncogenic pathways for improved therapeutic intervention and designing better drugs for targeting EZH2 in CLL. Overall design: Investigating the target genes for EZH2 and H3K27me3 enrichment using ChIP seq in chronic lymphocytic leukemia patient samples from age matched healthy individuals.