Strategies to re-express epigenetically silenced p15INK4b and p21WAF1 genes in acute myeloid leukemia

Abstract

p15INK4B and p21WAF1 are TGFβ targets that are silenced in leukemia by epigenetic mechanisms involving DNA methylation and/or histone modifications. Mechanisms for establishing and maintaining epigenetic silencing of p15INK4B and p21WAF1 are not well established. The reversible nature of epigenetic modifications has lead to the development of drugs that target DNA methyltransferases, histone deacetylases and histone methyltransferases, which have been used to re-express aberrantly silenced genes in leukemia. Recently, non-coding RNA, referred to as natural antisense transcripts (NATs), have been implicated in the regulation of epigenetic modifications. Here, we review epigenetic mechanisms for silencing p15INK4B and p21WAF1 and the role of NATs in this process. We also review epigenetic drugs and drug combinations used to re-express p15INK4B and p21WAF1. Lastly, we discuss the potential use of NATs to target the activity of epigenetic drugs to specific genes and to permanently re-express epigenetically silenced genes. © 2010 Landes Bioscience.