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 NPM1c+ 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(+) 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.
Highlights
Acetylation–deacetylation is among the several posttranslational modifications of the histones involved in regulating gene expression [1]
Our findings demonstrate that combined treatment with panobinostat and JQ1 is synergistically active against human acute myelogenous leukemia (AML) blast progenitor cells (BPC), including those with mutant NPM1cþ or mixed lineage leukemia (MLL) fusion oncoprotein with coexpression of FLT3-ITD
We discovered that cotreatment with panobinostat and JQ is more effective than each agent alone in significantly improving the survival of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice engrafted with AML cells expressing mutant nucleophosmin 1 (NPM1cþ) or MLL fusion oncoprotein with FLT3-ITD
Summary
Acetylation–deacetylation is among the several posttranslational modifications of the histones involved in regulating gene expression [1]. The resulting histone states or "marks" are recognized by the "reader" proteins, which assemble a complex of coregulatory proteins at the enhancers or promoters that initiate and regulate gene transcription [2, 3]. Among these "reader" proteins is the family of bromodomain and extra-terminal (BET) proteins, including BRD2 (bromodomain 2), BRD3, and BRD4 [4]. Authors' Affiliations: 1Houston Methodist Research Institute, Houston, Texas; 2Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah; and 3Dana-Farber Cancer Institute, Boston, Massachusetts. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
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