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J Cell Biochem. 2018 Nov 11. doi: 10.1002/jcb.28005. [Epub ahead of print]

BET inhibitors reduce cell size and induce reversible cell cycle arrest in AML.

Author information

1
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee.
2
Department of Biomedical Engineering, Morgridge Institute for Research, University of Wisconsin-Madison, Madison, Wisconsin.
3
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
4
Department of Biological Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee.
5
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
6
Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.

Abstract

Inhibitors of the bromodomain and extraterminal domain family (BETi) offer a new approach to treat hematological malignancies, with leukemias containing mixed lineage leukemia rearrangements being especially sensitive due to a reliance on the regulation of transcription elongation. We explored the mechanism of action of BETi in cells expressing the t(8;21), and show that these compounds reduced the size of acute myeloid leukemia cells, triggered a rapid but reversible G0 /G1 arrest, and with time, cause cell death. Meta-analysis of PRO-seq data identified ribosomal genes, which are regulated by MYC, were downregulated within 3 hours of addition of the BETi. This reduction of MYC regulated metabolic genes coincided with the loss of mitochondrial respiration and large reductions in the glycolytic rate. In addition, gene expression analysis showed that transcription of BCL2 was rapidly affected by BETi but this did not cause dramatic increases in cell death. Cell cycle arrest, lowered metabolic activity, and reduced BCL2 levels suggested that a second compound was needed to push these cells over the apoptotic threshold. Indeed, low doses of the BCL2 inhibitor, venetoclax, in combination with the BETi was a potent combination in t(8;21) containing cells. Thus, BET inhibitors that affect MYC and BCL2 expression should be considered for combination therapy with venetoclax.

KEYWORDS:

AML; AML1; BET; BRD4; ETO; JQ1; RUNX1; metabolism; venetoclax

PMID:
30417424
PMCID:
PMC6513713
[Available on 2020-05-11]
DOI:
10.1002/jcb.28005

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