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. 2009 Dec;33 Suppl 2(Suppl 2):S2-6.
doi: 10.1016/S0145-2126(09)70226-7.

In vitro basis for treatment with hypomethylating agents and histone deacetylase inhibitors: can epigenetic changes be used to monitor treatment?

Steven D Gore  1
Affiliations

In vitro basis for treatment with hypomethylating agents and histone deacetylase inhibitors: can epigenetic changes be used to monitor treatment?

Steven D Gore. Leuk Res. 2009 Dec.

Abstract

Hematopoietic disorders such as myelodysplastic syndromes (MDS) show a high frequency of methylation of tumor suppressor genes. DNA methyltransferase (DNMT) inhibitors such as azacitidine and decitabine are used to target DNA methylation in MDS patients. Combining these drugs with histone deacetylase (HDAC) inhibitors in vitro resulted in synergistic tumor suppressor gene re-expression. Several phase I trials have examined methylation, gene expression and DNA damage as markers of clinical response to DNMT and HDAC inhibitors, with conflicting results. Trials are ongoing to investigate early methylation changes and DNA damage markers to understand the mechanisms of these drugs and as potential predictors of clinical response.

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Figures

Fig. 1
Fig. 1
Hypermethylated genes in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) compared with normal CD34+ cells. A total of 736 unique genes were hypermethylated in 14 MDS patients compared with normal CD34+ cells from 8 controls [7]. Reproduced from Figueroa ME, et al. Blood 2009; doi: 10.1182/blood-2009-01-200519 © 2009 by The American Society of Hematology. All rights reserved.
Fig. 2
Fig. 2
DNA methylation and histone acetylation – epigenetic modulation of gene expression. Treatment with a DNA methyltransferase (DNMT) inhibitor can reverse the DNA methylation, resulting in re-expression of the genes. When histone deacetylase (HDAC) inhibitors are added, HDACs are blocked. These processes drive the chromatin into a more open, transcriptionally active, form.
Fig. 3
Fig. 3
Epigenetic modulation by decitabine. p15 gene expression in responders (complete response [CR]) versus non-responders (non-CR) [19]. Reproduced from Kantarjian H, et al. Blood. 2007;109:52–7 © 2007 by The American Society of Hematology. All rights reserved.
Fig. 4
Fig. 4
Plots of normalized gene expression in evaluable patients before and after one cycle of azacitidine and entinostat. Tested tumor suppressor genes included CDH-1, p15 (denoted CDKN2B), DAPK-1, SOCS-1, and two other genes (RASSF1 and CEBPA) frequently hypermethylated in myelodysplastic syndromes [6]. Reproduced from Fandy TE, et al. Blood. 2009;114:2764–73 © 2009 by The American Society of Hematology. All rights reserved.
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