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Effects of BRD4 inhibition in AML

ABSTRACT: The BET (bromodomain and extra terminal) protein family members including BRD4 bind to acetylated lysines on histones and regulate the expression of important oncogenes, e.g., MYC and BCL2. Here we demonstrate the sensitizing effects of the histone hyperacetylation inducing pan-histone deacetylase inhibitor (HDI) panobinostat (PS) on human AML blast progenitor cells (BPCs) to the BET protein inhibitor JQ1. Treatment with JQ1 but not its inactive enantiomer (R-JQ1) was highly lethal against AML BPCs expressing mutant NPM1c+ with or without co-expression of FLT3-ITD, or AML expressing MLL fusion oncoprotein. JQ1 treatment reduced binding of BRD4 and RNA polymerase II to the DNA of MYC and BCL2, and reduced their levels in the AML cells. Co-treatment with JQ1 and the HDAC inhibitor panobinostat (PS) synergistically induced apoptosis of the AML BPCs, but not of normal CD34+ hematopoietic progenitor cells. This was associated with greater attenuation of MYC and BCL2, while increasing p21, BIM and cleaved PARP levels in the AML BPCs. Co-treatment with JQ1 and PS significantly improved the survival of the NOD/SCID mice engrafted with OCI-AML3 or MOLM13 cells (p < 0.01). These findings highlight co-treatment with a BRD4 antagonist and an HDI as a potentially efficacious therapy of AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE51950 | GEO | 2014/01/01

SECONDARY ACCESSION(S): PRJNA225927

REPOSITORIES: GEO

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Project description:Epigenetic pathways regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. While chromatin alterations are, in principle, reversible and often amendable to drug intervention, the promise of targeting such pathways therapeutically has been hampered by our limited understanding of cancer-specific epigenetic dependencies. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukemia (AML) – an aggressive hematopoietic malignancy often associated with aberrant chromatin states. By screening a custom shRNA library targeting known chromatin regulators in a genetically defined AML mouse model, we identify the bromodomain-containing protein Brd4 as a critical requirement for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust anti-leukemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation. Extensive evaluation of JQ1-sensitivity in primary human leukemia samples and in established cell lines revealed a broad activity of this compound against diverse AML subtypes. These effects are, at least in part, due to a requirement for Brd4 in maintaining Myc expression and promoting aberrant self-renewal. Together, our results indicate that Brd4 is a promising therapeutic target in AML and identify a small molecule that efficiently targets Myc. These findings also highlight the utility of RNAi screening as a discovery platform for revealing epigenetic vulnerabilities for direct pharmacologic intervention in cancer. In order to understand downstream targets of Brd4, we performed array in murine or human MLL-AF9/NrasG12D cell line under the condition that Brd4 was suppressed by using shRNAs or the small molecule inhibitor JQ1. To test the hypothesis that Myc might be an important target of Brd4, we performed arrary on murine ectopic Myc overexpression MLL-AF9/NrasG12D cell under JQ1 treatment.

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Effects of BRD4 inhibition in AML

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