Beyond genetics--the emerging role of epigenetic changes in hematopoietic malignancies.
The term epigenetic refers to a heritable change in gene expression that is mediated by mechanisms other than alterations in the primary nucleotide sequence. DNA methylation at cytosine bases that are located 5' to guanosine within a CpG dinucleotide is the main epigenetic modification in humans. Patterns of DNA methylation 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 is associated with transcriptional inactivation and represents, in addition to genetic aberrations, an important mechanism of gene silencing in the pathogenesis of hematopoietic malignancies. This epigenetic phenomenon acts as an alternative to mutations and deletions to disrupt tumor suppressor gene function. A large number of genes involving fundamental cellular pathways may be affected in virtually all types of human cancer by aberrant CpG island methylation in association with transcriptional silencing. Altered methylation patterns can be used as biomarkers for cancer detection, assessment of prognosis, and prediction of response to antitumor treatment. Furthermore, clinical trials using epigenetically targeted therapies have yielded promising results for acute and chronic leukemias as well as for myelodysplastic syndromes. The exploration of our growing knowledge about epigenetic aberrations may help develop novel strategies for the diagnosis and treatment of hematopoietic malignancies in the future.
Medizinische Klinik IV, Universitaetsklinikum Aachen, Aachen, Germany.
Oliver
O
Galm
Manel
M
Esteller
D019175:DNA Methylation; D044127:Epigenesis, Genetic; D019337:Hematologic Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D006801:Humans