The fundamental role of epigenetics in hematopoietic malignancies

The term epigenetics defines a heritable alteration in gene expression without an accompanying change in primary DNA sequence. Two major mechanisms that foster epigenetic changes are DNA methylation at cytosine bases within a CpG dinucleotide and post-translational histone modifications. Disruption of the balanced epigenetic network may have significant impact on chromatin structure and transcriptional activity. DNA methylation patterns are profoundly deranged in human cancer and comprise genome-wide losses as well as regional gains in DNA methylation. Hypermethylation of CpG islands within gene promoter regions in collaboration with deacetylation and other modifications of key histone amino acids is associated with transcriptional inactivation and represents, in addition to genetic aberrations, an important mechanism of gene silencing in the pathogenesis of human cancer. These epigenetic events act as alternatives to mutations and deletions to disrupt tumor suppressor gene function. A large number of genes involving fundamental cellular pathways may be affected by aberrant CpG island methylation in association with transcriptional silencing in virtually all. tumor types. Altered DNA methylation patterns may serve as biomarkers for cancer detection, assessment of prognosis, and prediction of response to therapy. Furthermore, clinical trials using epigenetically targeted therapies have yielded promising results in hematopoietic malignancies. The ongoing exploration of basic events involved in altered gene transcription patterns and continued clinical investigative studies are helping to develop novel strategies for the diagnosis, prevention, and treatment of human cancer. (c) 2005 Elsevier Ltd. All rights reserved.