Histone deacetylase 3 (HDAC3) contributes to the regulation of gene expression, chromatin structure, and genomic stability. Because HDAC3 associates with oncoproteins that drive leukemia and lymphoma, we engineered a conditional deletion allele in mice to explore the physiological roles of Hdac3 in hematopoiesis. We used the Vav-Cre transgenic allele to trigger recombination, which yielded a dramatic loss of lymphoid cells, hypocellular bone marrow, and mild anemia. Phenotypic and functional analysis suggested that Hdac3 was required for the formation of the earliest lymphoid progenitor cells in the marrow, but that the marrow contained 3-5 times more multipotent progenitor cells. Hdac3 -/-stem cells were severely compromised in competitive bone marrow transplantation. In vitro, Hdac3 -/-stem and progenitor cells failed to proliferate, and most cells remained undifferentiated. Moreover, one-third of the Hdac3 -/-stem and progenitor cells were in S phase 2 hours after BrdU labeling in vivo, suggesting that these cells were impaired in transit through the S phase. DNA fiber-labeling experiments indicated that Hdac3 was required for efficient DNA replication in hematopoietic stem and progenitor cells. Thus, Hdac3 is required for the passage of hematopoietic stem/progenitor cells through the S phase, for stem cell functions, and for lymphopoiesis.

Hdac3 is a key target for Hdac inhibitors that are efficacious in cutaneous T cell lymphoma. Moreover, the regulation of chromatin structure is critical as thymocytes transition from an immature cell with open chromatin to a mature T cell with tightly condensed chromatin. To define the phenotypes controlled by Hdac3 during T cell development, we conditionally deleted Hdac3 using the Lck-Cre transgene. This strategy inactivated Hdac3 in the double-negative stages of thymocyte development and caused a significant impairment at the CD8 immature single-positive (ISP) stage and the CD4/CD8 double-positive stage, with few mature CD4؉ or CD8 ؉ single-positive cells being produced. When Hdac3 ؊/؊ mice were crossed with Bcl-xL-, Bcl2-, or TCR␤-expressing transgenic mice, a modest level of complementation was found. However, when the null mice were crossed with mice expressing a fully rearranged T cell receptor ␣␤ transgene, normal levels of CD4 single-positive cells were produced. Thus, Hdac3 is required for the efficient transit from double-negative stage 4 through positive selection.

The dynamic balance between histone acetylation and deacetylation is an important epigenetic mechanism controlling gene expression, and is associated with the etiology and progression of many human diseases. Early success of histone deacetylase (HDAC) inhibition in the treatment of hematological cancers paved the way for the development and testing of many different pan/global histone deacetylase inhibitors (HDIs). Dose limiting toxicities in these early trials, coupled with increased understanding of the differential expression patterns of HDACs in different tissues and disease states, led to the emergence of more specific HDIs that target specific HDAC classes and isotypes. Whereas a large number of clinical trials have been undertaken using pan-HDIs, which have demonstrated varying success in the treatment of hematological and solid malignancies, both as single agents and in combination with other drugs, there have been far fewer undertaken with the emerging repertoire of specific HDIs, which could potentially overcome the limitations seen in the pan inhibitors. In this review we describe the classification and development of HDIs as well the roles of HDACs in cancers, and the rationale behind moving toward more selective inhibition. We then examine the clinical efficacy of both pan-and specific HDI treatment by reviewing a number of clinical trials, focusing on hematological malignancies, where numerous trials have demonstrated single agent and combinatory efficacy, as well as breast cancers, where fewer trials have been undertaken showing limited efficacy, but also where promising pre-clinical findings necessitate further clinical investigation.