Growing evidence links abnormal epigenetic control to the development of hematological malignancies. Accordingly, inhibition of epigenetic regulators is emerging as a promising therapeutic strategy. The acetylation status of lysine residues in histone tails is one of a number of epigenetic post-translational modifications that alter DNA-templated processes, such as transcription, to facilitate malignant transformation. Although histone deacetylases are already being clinically targeted, the role of histone lysine acetyltransferases (KAT) in malignancy is less well characterized. We chose to study this question in the context of acute myeloid leukemia (AML), where, using in vitro and in vivo genetic ablation and knockdown experiments in murine models, we demonstrate a role for the epigenetic regulators CBP and p300 in the induction and maintenance of AML. Furthermore, using selective small molecule inhibitors of their lysine acetyltransferase activity, we validate CBP/p300 as therapeutic targets in vitro across a wide range of human AML subtypes. We proceed to show that growth retardation occurs through the induction of transcriptional changes that induce apoptosis and cell-cycle arrest in leukemia cells and finally demonstrate the efficacy of the KAT inhibitors in decreasing clonogenic growth of primary AML patient samples. Taken together, these data suggest that CBP/p300 are promising therapeutic targets across multiple subtypes in AML.

Angiogenesis is critical to the growth and regeneration of tissue but is also a key component of tumor growth and chronic inflammatory disorders. Endoglin plays a key role in angiogenesis by modulating cellular responses to transforming growth factor-␤ (TGF-␤) signaling and is upregulated in proliferating endothelial cells. To gain insights into the transcriptional hierarchies that govern endoglin expression, we used a combination of comparative genomic, biochemical, and transgenic approaches. Both the promoter and a region 8 kb upstream of exon 1 were active in transfection assays in endothelial cells. In transgenic mice, the promoter directed low-level expression to a subset of endothelial cells. By contrast, inclusion of the ؊8 enhancer resulted in robust endothelial activity with additional staining in developing ear mesenchyme. Subsequent molecular analysis demonstrated that both the ؊8 enhancer and the promoter depend on conserved Ets sites, which were bound in endothelial cells in vivo by Fli-1, Erg, and Elf-1. This study therefore establishes the transcriptional framework within which endoglin functions during angiogenesis. IntroductionEndoglin is a transmembrane glycoprotein that is expressed predominantly in endothelial cells and is critical for the normal development of blood vessels. 1 Endoglin-null mice die in utero with defects in vascular remodeling, [2][3][4] and haploinsufficiency of the gene in humans is associated with type 1 hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant disorder characterized by bleeding from vascular malformations in the skin, mucosa, and viscera (reviewed in Lebrin et al 5 and Abdalla and Letarte 6 ).Endoglin functions as an accessory receptor for members of the transforming growth factor-␤ (TGF-␤) superfamily of cytokines. 7 The TGF-␤ superfamily includes the TGF-␤ isoforms, nodal, activins, bone morphogenetic proteins (BMPs), and other related factors, which serve diverse functions during embryonic development and tissue homeostasis in the adult (reviewed in Massague 8 ). These cytokines assemble a primary receptor complex made up of type I and type II receptors on the surface of cells and control gene expression by receptor mediated phosphorylation of SMAD proteins. The type I receptors confer signal specificity by preferential phosphorylation of SMAD2/3 or SMAD1/5/8 isoforms, which broadly engage different binding partners and act on separate sets of target genes. Ancillary nonsignaling receptors such as endoglin regulate the pathway by selectively facilitating the binding of subsets of the TGF-␤ family members to the primary receptor complex. 9 Endoglin can also influence the cellular response to a particular cytokine by its preferential interaction with certain type I receptors. ALK1 is one such receptor, and mutations in this gene result in type 2 HHT, a clinical disorder that closely resembles that caused by mutations in the endoglin gene. 10 The endothelium is intimately involved in the development and progression of a number of pathologies, i...