Targeting aberrant transcriptional repression in acute myeloid leukemia.

Histone acetyltransferase (HAT) and histone deacetylase (HDAC) activities determine the acetylation status of histones, and have the ability to regulate gene expression through chromatin remodeling. Aberrant histone acetylation is known to play a key role in leukemogenesis. A common biologic feature, shared by genetically heterogeneous acute myeloid leukemias (AML), is a block of hematopoietic differentiation by the fusion proteins produced by chromosomal translocations. In many cases, a DNA binding fusion protein, which abnormally interacts with transcriptional co-regulators and increases local concentration of HDAC complexes, imposes a transcriptional repressive state on target gene promoters, which may become refractory to physiologic stimuli. To target this transcriptional repression, HDAC inhibitors (HDACI) have been developed, which are thought to derepress a set of genes whose transcriptional activation induces cell-cycle arrest, apoptosis and cellular differentiation and thus anti-tumoral activity. Therefore, HDACI might be utilized as effective antileukemic agents, and are currently under clinical trials.