Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human acute myelogenous leukemia cells

Warren Fiskus, Sunil Sharma, Jun Qi, John A. Valenta, Leasha J. Schaub, Bhavin Shah, Karissa Peth, Bryce P. Portier, Melissa Rodriguez, Santhana G T Devaraj, Ming Zhan, Jianting Sheng, Swaminathan P. Iyer, James E. Bradner, Kapil N. Bhalla

Research output: Contribution to journalArticle

132 Scopus citations

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 againstAMLBPCs expressing mutant NPM1c with or without coexpression of FLT3-ITD orAMLexpressing mixed lineage leukemia fusion oncoprotein. JQ1 treatment reduced binding ofBRD4 andRNApolymerase 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+ 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 anHDACinhibitor as a potentially efficacious therapy of AML.

Original languageEnglish (US)
Pages (from-to)1142-1154
Number of pages13
JournalMolecular Cancer Therapeutics
Volume13
Issue number5
DOIs
StatePublished - May 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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