Clinical development of demethylating agents in hematology

Abstract

The term epigenetics refers to the heritable changes in gene expression that are not associated with a change in the actual DNA sequence. Epigenetic dysregulation is linked to the pathogenesis of a number of malignancies and has been studied extensively in myelodysplastic syndromes and acute myeloid leukemia. DNA methylation is frequently altered in cancerous cells and likely results in transcriptional silencing of tumor suppressor genes. Re-expression of these genes by inhibition of the DNA methyltransferases has been successful in the treatment of benign and malignant disease. In this Review, we discuss the clinical development of demethylating agents in hematology, with a focus on azacitidine and decitabine.

Figure 1. Biological mechanism of action of azacitidine (AZA) and decitabine (DAC).

(A) Structures of cytidine, azacitidine, and decitabine. (B) DNMTs methylate cytidine. Methylation of cytidine in gene promoter regions blocks the binding of transcription factors, leading to epigenetic silencing. DNMTs aberrantly methylate tumor suppressor genes in hematological malignancies and other cancers. (C) Azacitidine is converted to decitabine and is then incorporated into DNA in place of cytidine during replication. Both azacitidine and decitabine inactivate DNMTs, preventing gene methylation. The resultant hypomethylation leads to the transcription of previously silenced genes. Notably, azacitidine, but not decitabine, can be incorporated directly into RNA, inhibiting protein synthesis.