Epigenetic regulation in myelodysplastic syndromes: implications for therapy

Abstract

Alongside current single-agent epigenetic regimens, combination therapies represent potentially effective options for intermediate-2 and high-risk MDS. Methylation profiles and gene mutation predictors provide promising areas of development for monitoring MDS disease progression and outcome, while targeting microRNA dysregulation represents an important therapeutic goal.

The Epigenetic Drug 5-Azacytidine Interferes with Cholesterol and Lipid Metabolism

“…Although clinical benefits of 5-AzaC are associated with re-expression of hypermethylated tumor suppressor genes in MDS patients, its therapeutic mechanism remains largely undefined (2,7,40). Therefore, we propose that, in addition to DNA hypomethylation, inhibition of CTP synthesis and FIGURE 8.…”

Epigenetics in Cancer: The Myelodysplastic Syndrome as a Model to Study Epigenetic Alterations as Diagnostic and Prognostic Biomarkers

“…Knudson model of the "two hits" provides the basis of the concept of a multistep pathogenesis in the development of MDS, where loss or inactivation of only one allele is not sufficient to result in the development of tumors or expansion of a malignant clone. In fact, MDS in early stages with its relatively www.intechopen.com slow (but with increased tendency) to AML progression represents a prototype of the multistep concept in leukemogenesis with accumulation of cellular and molecular defects during the initiation and disease progression (Vigna et al, 2011).…”

“…It has been shown in MDS a high prevalence of methylation for the tumor suppressor genes p15 INK4B , cadherin 1 (CDH1), death associated protein kinase (DAPK) and suppressor of cytokine signaling (SOCS-1). Some methylation patterns in specific genes in MDS can predict poor prognosis even in early stage of the disease (Aggerholm et al, 2006;Bejar et al, 2011;Vigna et al, 2011). Hence, epigenetic changes have been implicated as potential mechanisms in the pathogenesis and progression of MDS, which has already resulted in promising therapeutic approaches in a subset of patients.…”

“…Although responses using HDAC inhibitors alone in MDS have been modest, preclinical data drives clinical trials in which they are utilized in combination with DNA methyltransferase inhibitors. Combination therapy offers the possibility of hematologic improvement and remission to MDS patients with previously untreatable disease (Vigna et al, 2011).…”

“…It is important to characterize the cancer related genes regulated by each of the DNMTs and develop DNMT gene-specific inhibitors. Moreover, treatment duration and maintenance therapy of using these agents require further investigation (Vigna et al, 2011).…”