Genome-Wide Epigenetics in Myeloid Leukemias.

While the role of genetic alterations in cancer is well-recognized, epigenetic deregulation has only recently been identified as a hallmark of malignant transformation. The term “epigenetic” refers to a heritable regulation of gene expression that is not dependent on changes in the DNA sequence. These epigenetic modifications – including but not limited to DNA methylation and covalent modifications of histone tails – play a crucial role in determining chromatin structure and gene expression. Abnormal epigenetic regulation can lead to aberrant chromatin structure and deregulation of transcriptional activity. Epigenetic lesions can affect cancer-related genes, such as CDKN2B, CDKN2A, RB, and BRCA1, and it is not rare for epigenetic lesions to accompany genetic mutations of these and other genes, suggesting that epigenetic deregulation can form a part of the multi-step process of oncogenesis. An alteration in the distribution of DNA methylation has been demonstrated in AML as well as in other malignancies. Generally, intergenic DNA methylation is reported to decrease and promoter methylation to increase. Hypomethylation of DNA can lead to genomic instability and further increase the number of genetic lesions, while promoter hypermethylation has been associated with aberrant silencing of tumor suppressor genes. Altered levels of acetylation at specific histone residues were also shown to be associated with aberrant chromatin structure and gene deregulation in AML. Several oncogenic transcription factors and fusion proteins, such as PML-RARalpha, and AML1-ETO, can introduce aberrant epigenetic programming in myeloid cells through recruitment of epigenetic modifying enzymes to their target genes. However, the emerging field of epigenomic profiling has yielded evidence that epigenetic deregulation in AML is more profound and cannot always be linked to the presence of a given fusion protein. The mechanisms leading to genome-wide epigenetic deregulation still remain largely unidentified, although environmental factors and aging can contribute to this process. Current epigenetic profiling studies have revealed that DNA methylation or histone modification patterns can identify biologically distinct forms of AML that may not be readily identified through other methods. New data suggest that specific DNA methylation profiles may be associated with response to therapeutic agents, including epigenetic-targeted drugs. Numerous epigenetic candidate biomarkers have been recently described in both myeloid and lymphoid malignancies. Integrative analysis of DNA methylation, histone modifications, and gene expression may synergize to identify in far greater depth than single platform studies differences in gene regulation among leukemias. Overall, the emerging field of epigenomics provide a new opportunity to more accurately identify biological variation and therapeutically target acute myeloid leukemias.