Epigenetic regulation of hematological malignancies

The field of epigenetics consists of all heritable changes of the transcriptome without altering the primary DNA sequence. DNA methylation of cytosine bases within a CpG dinucleotide and post-translational histone modifications (acetylation, methylation, phosphorylation, ubiquitination,...) represent the two best documented epigenetic modifications and are broadly acknowledged to co-operate intensively to control the organization of the chromatin architecture and hence transcriptional regulation. Generally, DNA methylation is repressive for transcription, while histone modifications can be both active or repressive depending on the type, degree and the site. In mammalians, CpG-rich regions (CpG islands) located at the intergenic regions are heavily methylated in normal cells and are associated with repressive histone marks thus governing genomic stability. In contrast, most of the promoter associated CpGs islands are unmethylated and associated with permissive histone marks thus permitting gene expression, except for tissue specific genes or genes involved in X chromosome inactivation and imprinting. Consequently, epigenetic modifications play a crucial role in normal development and are essential for maintaining cell identity and normal functionality. In most cancers, including myeloid and lymphoid malignancies, the epigenetic landscape is completely disrupted. Intergenic regions have become severely hypomethylated and associated with active PTM marks leading to genomic instability, while the promoter-associated CpG islands of tumor suppressor genes are often hypermethylated and associated with repressive PTM marks resulting in loss-of-function. The fundamental difference between epigenetic and genetic alterations is the reversible nature of the former, making chromatin-modifying enzymes, referred to as epigenetic "writers" and "erasers", today one of the most promising and pursued drug targets. Already, inhibitors of histone deacetylases (HDACi; panobinostat, vorinostat,...) and DNA methyltransferases (DNMTi; azacytidine and decitabine) have demonstrated substantial clinical efficacy in hematological malignancies (especially in MDS, AML and CML, but also in MM). Nevertheless, despite these encouraging preliminary results, to date single-agent anti-tumor effects of these epigenetic modulating agents are only modest in most hematological malignancies. This can, in part, be explained by the fact that the pleiotropic mechanisms by which the epigenetic-modulating agents mediate their anti-tumor activity, especially in vivo, remain largely unknown. An interesting and complex issue is to what extent the neoplastic cells are epigentically modified after treatment in vivo where the cells are protected by the surrounding cells of the tumor microenvironment. Consequently, these agents remain under intensive investigation and pre(clinical) studies are ongoing to investigate new dosing schedules, routes of administration and combination with other (chemotherapeutic) agents. In the first part of the presentation an overview of the commonly observed epigenetic aberrations in hematological malignancies and the obtained results of clinical trials will be given. In a second part, we then discuss molecular events underlining the antitumor effects of HDACi and DNMTi and strategies to improve responsiveness to epigenetic modulating drugs using MM as a model for epigenetic dysregulation in hematological malignancies.