Epigenetic Dysregulation in Lymphoid Malignancies

Abstract

AbstractAbstract SCI-29Greater understanding of the role of the epigenetic mechanisms and cancer cell epigenome in the pathogenesis of cancer in general and lymphoid malignancies in particular has emerged, which is yielding insights into how to therapeutically target these novel mechanisms. Epigenetic mechanisms include histone modifications, DNA methylation, nucleosome remodeling and small non-coding RNAs. In transformed cells, the methylome involves global DNA hypomethylation mostly targeting DNA repeats, and hypermethylation of CpG islands in the promoter regions of TSGs. For example, methylation and silencing of cell cycle dependent kinase inhibitors p16 and p15, and of DNA repair protein MGMT, is observed in lymphoma. A disequilibrium in the lysine (K) acetylation/deacetylation of the N-terminal tail of the core histone (H) proteins due to increased histone deacetylase (HDAC) activity leads to aberrant transcription repression of genes involved in regulation of proliferation and differentiation of lymphoid progenitors in lymphoid malignancies. Additionally, increased HDAC levels and activity may directly deacetylate and modify the transcriptional activity of transcription factors, or HDACs may be recruited along with co-repressors by transcriptional repressors such as Bcl-6 to the promoters of the repressed genes in lymphoma. Histone lysine methylation, regulated by the reciprocal activity of a specific histone methyl transferase (HMTs) and histone de-methylase, also modifies gene expression based on the lysine residue that is affected. For example, increased levels and activity of the polycomb repressive complex (PRC) 2 protein EZH (enhancer of zeste) 2, a histone methyl transferase induces the repressive chromatin mark H3K27 trimethylation (me3), which is erased by the demethylase, UTX. Mutations in EZH2 and UTX have been observed in transformed cells. Conversely, the methylation status of the permissive chromatin mark H3K4me3 and gene expression is reciprocally controlled by the HMTase, MLL, and the demethylases JARID1A and LSD1. PRC1 protein, BMI-1, is over-expressed and implicated in lymphoid malignancies. Genetic abnormalities of cell fate transcription factors (CFTFs), e.g., MYB, PAX5 and IKAROS, which recruit PRC1 and PRC2 complexes and their member proteins, e.g., BMI and EZH2, also deregulate the expression of developmentally regulated genes involved in stem cell behavior, related to self-renewal, proliferation and differentiation of transformed cells. PRC proteins EZH2 and BMI, in turn, can recruit DNMTs and promote de novo DNA methylation of TSGs. Levels and activity of the non-coding small (MiRs 101 and 26a for EZH2; MiR 29 for DNMT3a and DNMT3b; and MiR15a and 16 for BMI) may also be deregulated in transformed cells. Interestingly, the levels of MiRs are epigenetically regulated. Collectively, the complex interplay of the epigenetic mechanisms in the pathogenesis of lymphoid malignancies underscores the importance of targeting the deregulated mechanisms in a combinatorial fashion. Inhibitors of chromatin modifying enzymes including HDACs and DNMTs are approved for therapy by the FDA and, given alone or in combination, have shown efficacy in clinical trials in hematologic malignancies. Combined inhibition of EZH2 and HDACs also displays anti-lymphoma and anti-leukemia synergy. In the presentation, the emerging knowledge related to the role of epigenetic mechanisms in the pathogenesis of lymphoid malignancies, as well as the potential for combined therapeutic targeting of the deregulated mechanisms will be highlighted. Disclosures:Bhalla:Novartis: Honoraria, Research Funding; Merck: Honoraria.