Epigenetics and the Role of Methylation in MDS

Cancer has been shown to be a genetically influenced disease, frequently involving some degree of mutations and chromosomal deletions. These problems are difficult to address and cannot be resolved without introducing new genetic material. In contrast, epigenetic changes, which also have been implicated in the genesis of cancer, are potentially reversible.1,2

Epigenetic changes are heritable changes to the DNA and chromatin that lead to modified expression.1,2 Their possible reversibility has recently made them the subject of intensive scientific scrutiny and research.1

One of the most important epigenetic modulations is DNA methylation, which influences tissue and stage-specific gene regulation, genomic imprinting and X-chromosome inactivation.2 Global hypomethylation and regional hypermethylation have been shown to occur during tumorigenesis and to be tumor-specific.2 Problematic cytosine methylation has been well-proven to be a common epigenetic change in cancer.1

Methylation problems arise in neoplastic cells as a result of global dysregulation of DNA methyltransferase I, which is a key protein for maintaining DNA methylation structures. Abnormalities also arise from regional hypermethylation of CpG dinucleotides in gene promoter regions. In normal cells, CpG clusters are protected from methylation, but in cancer cells they are highly methylated.1 This feature in promoter cells makes them appealing targets for therapeutic intervention.1

The attraction of DNA methylation as a therapeutic target encompasses MDS because DNA hypermethylation is suspected of being involved in leukemogenesis. The calcitonin gene is hypermethylated in many hematopoietic malignancies, for instance, in 65% of myelodysplastic syndromes (MDS) and in 95% of leukemias. It also unfavorably influences outcomes for acute lymphoblastic leukemia.2 Further, methylation of the p15 promoter has been shown to be relevant in 35% of MDS samples and to increase in frequency as the disease progresses.1

The guiding hypothesis of methylation investigation is that a therapy that targets DNA methylation may improve and perhaps even reverse this epigenetic change, thereby providing great potential benefit to patients with hematopoietic malignancies.1

Visit other pages in this section to learn more about MDS. For management strategies, current treatment options and the latest developments in MDS treatment, visit the following sections:

• Managing Myelodysplastic Syndromes
• Treating Myelodysplastic Syndromes