The epigenetic regulators CBP and p300 facilitate leukemogenesis and represent therapeutic targets in acute myeloid leukemia

Abstract

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.

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“…However, the context-dependent functions of KATs in hematologic malignancies suggest that caution be used evaluating agents targeting KATs. Pan KAT inhibitors have been shown to induce apoptosis and cell-cycle arrest in multiple AML cell lines and decrease the clonogenic growth of primary AML cells from patients, consistent with a pro-oncogenic role in various subtypes of AML [6]. However, our genetic study indicates that p300 can serve as a tumor suppressor gene in MDS, thus KAT's inhibitor may not benefit certain cohorts of patients.…”

MED12 Regulates HSC-Specific Enhancers Independently of Mediator Kinase Activity to Control Hematopoiesis

“…Since mutations driving CLL also reside in the N terminus (Kämpjärvi et al, 2015), it is tempting to speculate that MED12 gain-of-function mutations could give rise to leukemia, as MED12 loss of function would lead to bone marrow failure according to our research. Interestingly, several of the co-activators interacting with MED12 in HSPCs are also frequently mutated in leukemia and lymphoma, including P300 , CBP , KMT2D , WDR5 , and KMD6A (Figure 7A, red circle) (Giotopoulos et al, 2016; Ntziachristos et al, 2012; Ortega-Molina et al, 2015). Future work will test whether these genetic events induce cellular transformation by modulating enhancer-promoter interactions and transcription factor activity.…”

Modulation of p300/CBP Acetylation of Nucleosomes by Bromodomain Ligand I-CBP112

“…2–8 Dysregulation of p300/CBP by mutation, altered expression, or other mechanisms has been linked to disease states, including various malignancies such as acute leukemias and prostate cancer. 1,5,6,9–14 Furthermore, p300/CBP is critical in development as evidenced by the genetic disorder Rubinstein-Taybi syndrome, which occurs with loss of function mutations in single alleles of either p300 or CBP. 15 …”

“…19 Inhibitors of p300/CBP HAT activity have been developed and are under investigation as therapeutics for a number of diseases. 5,10,14,22,23 Additional key p300/CBP domains include a well-characterized bromodomain that is just N-terminal to the HAT domain and can bind acetyl-Lys-containing peptides. The bromodomain is one of the most highly conserved domains in p300 and CBP, possessing 96% sequence identity.…”