Role of DNA Methylation in the Pathogenesis and Treatment of Myelodysplastic Syndromes

Hina Khan, Cristina Vale, Tushar Bhagat, Amit K. Verma

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

The myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by ineffective hematopoiesis and increased risk of transformation to acute myeloid leukemia (AML). Even though mutations have been shown to occur in MDS, a notable proportion of these affect genes involved in epigenetic maintenance, suggesting a dominant role of epigenomic dysregulation in the pathogenesis of MDS. Aberrant DNA methylation is the dominant and most well-studied epigenetic alteration in MDS. Various genes, including cell cycle regulators, apoptotic genes, and DNA repair genes, are epigenetically silenced and have roles in pathogenesis and transformation to leukemia. The involvement of these genes in MDS pathophysiology and prognosis is reviewed and reveals distinct methylation patterns between high- and low-risk subsets of this disease. Furthermore, DNA methyltransferase (DNMT) inhibitors azacitdine and decitabine are approved for treatment even though the optimal dosing strategies are still being developed. We have reviewed the mechanisms of action of these agents in MDS and show that demethylation may not correlate well with their efficacy, thus suggesting alternative modes of action. We also show that DNMT inhibitors may have potent anti-leukemic stem cell effects at lower doses and also review the mechanisms of resistance to these agents. Altogether, these studies show that even though DNA methylation has been studied extensively in MDS, its role in prognosis and response to therapy is still unclear. The use of deep sequencing and genome-wide methylome analysis will potentially uncover prognostic signatures and reveal the complexity of epigenetic dysregulation in this disease.

Original languageEnglish (US)
Pages (from-to)16-37
Number of pages22
JournalSeminars in Hematology
Volume50
Issue number1
DOIs
StatePublished - Jan 2013

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Myelodysplastic Syndromes
DNA Methylation
Epigenomics
decitabine
Methyltransferases
Genes
High-Throughput Nucleotide Sequencing
cdc Genes
DNA
Hematopoiesis
Regulator Genes
Acute Myeloid Leukemia
DNA Repair
Methylation
Leukemia
Stem Cells
Maintenance
Genome
Mutation

ASJC Scopus subject areas

  • Hematology

Cite this

Role of DNA Methylation in the Pathogenesis and Treatment of Myelodysplastic Syndromes. / Khan, Hina; Vale, Cristina; Bhagat, Tushar; Verma, Amit K.

In: Seminars in Hematology, Vol. 50, No. 1, 01.2013, p. 16-37.

Research output: Contribution to journalArticle

Khan, Hina ; Vale, Cristina ; Bhagat, Tushar ; Verma, Amit K. / Role of DNA Methylation in the Pathogenesis and Treatment of Myelodysplastic Syndromes. In: Seminars in Hematology. 2013 ; Vol. 50, No. 1. pp. 16-37.
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