Epigenetics in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a disease characterized by uncontrolled proliferation of clonal neoplastic hematopoietic precursor cells. This leads to the disruption of normal hematopoiesis and bone marrow failure. Major breakthroughs in the past have contributed to our understanding of the genetic failures and the changed biology in AML cells that underlie the initiation and progression of the disease. It is now recognized that not only genetic but also epigenetic alterations are similarly important in this process. Since these alterations do not change the DNA sequences and are pharmacologically reversible, they have been regarded as optimal targets for what is now known as epigenetic therapy. In this review, we will discuss our current understanding of normal epigenetic processes, outline our knowledge of epigenetic alterations in AML, and discuss how this information is being used to improve current therapy of this disease.

Figure 1

Mechanism of reactivation of silenced genes in cancer using azanucleosides and HDAC (histone deacetylase) inhibitors. Aberrant silencing of tumor-suppressor genes is maintained by factors that control chromatin states. DNMT (DNA methyltransferase) and HDAC enzymes cooperatively work to methylate DNA and deacetylate histones, respectively. Treatment with azanucleosides reduces DNMT activity and thus promotes net DNA demethylation (occurring during DNA replication or by active processes), while HDAC inhibitors promote a net gain of histone acetylation. In combination, these two therapies work synergistically to promote and maintain active chromatin states. HAT, histone acetyltransferase.