Highly Active Combination of BRD4 Antagonist and Histone Deacetylase Inhibitor against Human Acute Myelogenous Leukemia Cells

Abstract

The bromodomain and extra-terminal (BET) protein family members, including BRD4, bind to acetylated lysines on histones and regulate the expression of important oncogenes, for example, c-MYC and BCL2. Here, we demonstrate the sensitizing effects of the histone hyperacetylation-inducing pan-histone deacetylase (HDAC) inhibitor panobinostat on human acute myelogenous leukemia (AML) blast progenitor cells (BPC) to the BET protein antagonist JQ1. Treatment with JQ1, but not its inactive enantiomer (R-JQ1), was highly lethal against AML BPCs expressing mutant NPM1cþ with or without coexpression of FLT3-ITD or AML expressing mixed lineage leukemia fusion oncoprotein. JQ1 treatment reduced binding of BRD4 and RNA polymerase II to the DNA of c-MYC and BCL2 and reduced their levels in the AML cells. Cotreatment with JQ1 and the HDAC inhibitor panobinostat synergistically induced apoptosis of the AML BPCs, but not of normal CD34 þ hematopoietic progenitor cells. This was associated with greater attenuation of c-MYC and BCL2, while increasing p21, BIM, and cleaved PARP levels in the AML BPCs. Cotreatment with JQ1 and panobinostat significantly improved the survival of the NOD/SCID mice engrafted with OCI-AML3 or MOLM13 cells (P < 0.01). These findings highlight cotreatment with a BRD4 antagonist and an HDAC inhibitor as a potentially efficacious therapy of AML. Mol Cancer Ther; 13(5); 1142-54. Ó2014 AACR.

Ectopic protein interactions within BRD4–chromatin complexes drive oncogenic megadomain formation in NUT midline carcinoma

“…2D). BET inhibition also leads to a reduction in ZNF532 expression in various non-NMC tissues (18)(19)(20)(21)(22). These results demonstrate that ZNF532 expression is strongly dependent on BET bromodomain proteins such as BRD4, and especially on BRD4-NUT association with the locus in NMC patient cells.…”

Histone Deacetylases as New Therapeutic Targets in Triple-negative Breast Cancer: Progress and Promises

“…JQ1 is a bromodomain and extra-C terminal (BET) inhibitor and is reported to participate in the expression of oncogenes and tumor suppressor genes. JQ1 is in pre-clinical testing for the treatment of hematological malignancies and neuroblastoma (98)(99)(100). Researchers found that either JQ1 or mocetinostat treatment alone, inhibited the expression of genes involved in cell cycle regulation.…”

Epigenetic regulators and their impact on therapy in acute myeloid leukemia

“…[118][119][120] Combinations of HDAC inhibitor panobinostat with JQ1 inhibitors, EZH2 inhibitors or LSD1 inhibitors showed synergistically lethal effects on AML cells. [121][122][123] A recently presented phase 1 study, in which a short course of panobinostat was given in addition to the classical "7+3" induction chemotherapy in 22 patients >60 years with de novo AML or high-risk MDS, showed a CR/CRi rate of 40% and a median survival rate of 16 months in responders in this high-risk cohort.…”

“…121 Also, combinations of JQ1 with the HDAC inhibitor panobinostat increased apoptosis in human AML blast progenitor cells. 122 A more stable and soluble derivate of JQ1 for clinical application, JQ2 (TEN-010), is currently being tested in a phase I study in patients with AML and MDS (NCT02308761). The BRD4 inhibitor, GSK525762, has entered early clinical trials in patients with relapsed refractory hematological malignancies (NCT01943851).…”