BET inhibitors reduce cell size and induce reversible cell cycle arrest in AML
Year: 2018
Type: article
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 G 0 /G 1 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.
Source: Journal of Cellular Biochemistry
DOI: 10.1002/jcb.28005
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: American Cancer Society, Vanderbilt-Ingram Cancer Center, Institut National Du Cancer, National Institutes of Health, Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: Optical imaging of pancreas cancer organoids for drug development and personalized treatment, Functions of Histone Ubiquitination and Methylation, Cellular level optical metabolic imaging to predict drug response in cancer, (PQ7) Quantitative in vivo optical imaging of tumor heterogeneity, G3831037829, G5096230709, XFe96 Analyzer, G5550678384, G565149442, G5710101065, The Vanderbilt Institute for Clinical and Translational Research (VICTR) UL1, Role of AML1-ETO in Acute Leukemia, Establishing that Hdac3 is a therapeutic target in a subset of B cell Lymphoma, G7298206234, The Vanderbilt Institute for Clinical and Translational Research (VICTR), G8592270211, Regulation of transcription and tumor suppression by MTG family members, Molecular and Cellular Basis for Digestive Diseases, Biochemical and Chemical Training for Cancer Research, Cancer Center Support Grant
OpenAlex ID: W2901544597