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

Susu Zhang, Yue Zhao, Tiffany M. Heaster, Melissa A. Fischer, Kristy R. Stengel, Xiaofan Zhou, Haley Ramsey, Ming Ming Zhou, Michael R. Savona, Melissa C. Skala, Scott W. Hiebert

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7309-7322
Number of pages14
JournalJournal of Cellular Biochemistry
Volume120
Issue number5
DOIs
StatePublished - May 2019
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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