Abstract
The bromodomain and extra terminal (BET) family protein bromodomain containing protein 4 (BRD4) is an epigenetic regulator recently identified as a therapeutic target for several hematological cancers, notably mixed lineage leukemia-fusion acute myeloid leukemia (MLL-AML). Here, we show that the BRD4 bromodomain inhibitor JQ1 is highly active against the p53-wild-type Ontario Cancer Institute (OCI)-AML3 cell line which carries mutations in nucleophosmin (NPM1) and DNA methyltransferase 3 (DNMT3A) genes commonly associated with poor prognostic disease. We find that JQ1 causes caspase 3/7-mediated apoptosis and DNA damage response in these cells. In combination studies, we show that histone deacetylase (HDAC) inhibitors, the HDM2 inhibitor Nutlin-3, and the anthracycline daunorubicin all enhance the apoptotic response of JQ1. These compounds all induce activation of p53 suggesting that JQ1 might sensitize AML cells to p53-mediated cell death. In further experiments, we show that BRD4 associates with acetylated p53 but that this association is not inhibited by JQ1 indicating that the protein–protein interaction does not involve bromodomain binding of acetylated lysines. Instead, we propose that JQ1 acts to prevent BRD4-mediated recruitment of p53 to chromatin targets following its activation in OCI-AML3 cells resulting in cell cycle arrest and apoptosis in a c-MYC-independent manner. Our data suggest that BET bromodomain inhibition might enhance current chemotherapy strategies in AML, notably in poor-risk DNMT3A/NPM1-mutated disease.
Highlights
Several recent papers have demonstrated the therapeutic potential of targeted inhibition of bromodomaincontaining proteins in certain hematological malignancies including acute myeloid leukemia (AML) [1, 2] and multiple myeloma (MM) [3, 4]
We show that combined treatment with other compounds known to activate p53, namely histone deacetylase (HDAC) inhibitors, Nutlin-3 and daunorubicin, all potentiate the action of JQ1 on Ontario Cancer Institute (OCI)-AML3 cells suggesting JQ1-induced cell death is via a p53-mediated pathway that appears to involve a caspase 3/7-dependent mechanism
We show that bromodomain containing protein 4 (BRD4) associates with activated p53 suggesting that BRD4 inhibition by JQ1 may result in failed recruitment of p53 to chromatin leading to impaired DNA damage repair response, cell cycle arrest, and cell death
Summary
Several recent papers have demonstrated the therapeutic potential of targeted inhibition of bromodomaincontaining proteins in certain hematological malignancies including acute myeloid leukemia (AML) [1, 2] and multiple myeloma (MM) [3, 4]. Small molecule inhibitors of the bromodomain pocket, such as JQ1 and I-BET, disrupt bromodomain containing protein 4 (BRD4) recruitment to chromatin leading to downregulation of key oncogenes, notably cellular-myelocytomatosis oncogene (c-MYC) [1, 3, 4], BCL2, and CDK6 [2]. This results in reactivation of the p21 tumor suppressor [4] leading to cell cycle arrest and apoptosis of many, but not all,
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