Epigenetic mechanisms in AML - a target for therapy

Abstract

Epigenetics refers to a stable, mitotically perpetuated regulatory mechanism of gene expression without an alteration of the coding sequence. Epigenetic mechanism include DNA methylation and histone tail modifications. Epigenetic regulation is part of physiologic development and becomes abnormal in neoplasia, where silencing of critical genes by DNA methylation or histone deacetylation can contribute to leukemogenesis as an alternative to deletion or loss-of-function mutation. In acute myelogenous leukemia (AML), aberrant DNA methylation can be observed in multiple functionally relevant genes such as p15, p 73, E-cadherin, ID 4, RARbeta2. Abnormal activities of histone tail-modifying enzymes have also been seen in AML, frequently as a direct result of chromosomal translocations. It is now clear that these epigenetic changes play a significant role in development and progression of AML, and thus constitute important targets of therapy. The aim of targeting epigenetic effector protein or "epigenetic therapy" is to reverse epigenetic silencing and reactive various genes to induce a therapeutic effect such as differentiation, growth arrest, or apoptosis. Recent clinical studies have shown the relative safety and efficacy of such epigenetic therapies.