The histone methyltransferase EZH2 as a novel therapeutic target in Chronic Lymphocytic Leukemia

Two primary and interconnected epigenetic mechanisms are histone modifications and DNA methylation. Whereas DNA methylation is considered to be a very stable epigenetic modification, histone modifications are more labile. Levels of histone modifications are maintained by the balance between the activities of histone-modifying enzymes that add or remove specific modifications. As aberrant histone modification levels result from an imbalance in these modifying enzymes in diseased tissue, correcting the increased or decreased level of a particular enzyme could restore the natural equilibrium in the affected cells.

  • The histone methyltransferase EZH2 is the catalytic core protein in the Polycomb Repressor Complex 2 (PRC2), which catalyses the trimethylation of histone 3 lysine 27 (H3K27) and mediates gene silencing of target genes involved in fundamental cellular processes, such as cell fate decision, cell cycle regulation, senescence, cell differentiation and cancer.
  • In both solid tumors and hematopoietic malignancies, more aggressive subtypes display overexpression of EZH2 caused by different mechanisms (at genomic, transcriptional, post-transcriptional and post-translational levels), including reduced expression of miR-101, one of the so-called epi-miRNAs, a group of miRNAs which regulate the expression of components of the epigenetic machinery, also targeting EZH2.
  • EZH2 inhibitors were recently shown to result in reactivation of EZH2 repressed target genes, inhibit cell growth, and reduce tumor formation in various cancers, including diffuse large B cell lymphoma of the germinal center type.
  • Recently we reported (Papakonstantinou et al. Mol Med 2013) that EZH2 is also implicated in Chronic Lymhocytic Leukemia (CLL) pathogenesis. More specifically we gave evidence that EZH2 is implicated in shaping the distinct genetic and biological makeup of aggressive stereotyped CLL subset #1 versus indolent stereotyped CLL subset #4. As part of our ongoing research, we found that EZH2 is generally over-expressed in aggressive CLL, albeit with variability in expression levels between different disease subgroups. We showed that EZH2 confers a survival advantage to CLL cells and that pharmacological inhibition of EZH2 decreases CLL cell viability overtime, suggesting that the histone trimethylation catalytic activity of EZH2 is vital for CLL cell survival.