@article{a62dde9c387344deb1540c630798c7c3,
title = "BET inhibitors reduce cell size and induce reversible cell cycle arrest in AML",
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",
author = "Susu Zhang and Yue Zhao and Heaster, {Tiffany M.} and Fischer, {Melissa A.} and Stengel, {Kristy R.} and Xiaofan Zhou and Haley Ramsey and Zhou, {Ming Ming} and Savona, {Michael R.} and Skala, {Melissa C.} and Hiebert, {Scott W.}",
note = "Funding Information: We thank all the members of Hiebert Laboratory for helpful discussions, reagents, and advice. We thank the translational pathology, the hematological sample repository, flow cytometry, and VANTAGE Shared Resources for services and support. This study was supported by the T. J. Martell Foundation, the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation, National Institutes of Health (grants, RO1-CA109355, RO1-CA164605, and R01-CA64140) and core services performed through Vanderbilt Digestive Disease Research Center (grant, NIDDK P30DK58404) and the Vanderbilt-Ingram Cancer Center support (grant, NCI P30CA68485). KS was supported by 5 T32 CA009582-31 and a postdoctoral fellowship (PF-13-303-01-DMC) from the American Cancer Society. The project described was also supported by the National Center for Research Resources (grant, UL1 RR024975-01) and is now at the National Center for Advancing Translational Sciences (grant, 2 UL1 TR000445-06). This study was supported by grant 1S10OD018015-01A1 for the Seahorse Extracellular Flux Analyzer and Prep Station, housed in the Vanderbilt High-Throughput Screening Facility. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH). Dr. Savona receives grants, personal fees and non-financial support from Astex, Boehringer-Ingelheim, Celgene Karyopharm, Sunesis, Takeda, TG Therapeutics, Gilead, and Incyte Corporation that are unrelated to this work. Dr. Hiebert receives grants and personal fees from Incyte Corporation that are unrelated to this work. Funding Information: We thank all the members of Hiebert Laboratory for helpful discussions, reagents, and advice. We thank the translational pathology, the hematological sample repository, flow cytometry, and VANTAGE Shared Resources for services and support. This study was supported by the T. J. Martell Foundation, the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation, National Institutes of Health (grants, RO1‐ CA109355, RO1‐CA164605, and R01‐CA64140) and core services performed through Vanderbilt Digestive Disease Research Center (grant, NIDDK P30DK58404) and the Vanderbilt‐Ingram Cancer Center support (grant, NCI P30CA68485). KS was supported by 5 T32 CA009582‐31 and a postdoctoral fellowship (PF‐13‐303‐01‐DMC) from the American Cancer Society. The project described was also supported by the National Center for Research Resources (grant, UL1 RR024975‐01) and is now at the National Center for Advancing Translational Sciences (grant, 2 UL1 TR000445‐06). This study was supported by grant 1S10OD018015‐01A1 for the Seahorse Extracellular Flux Analyzer and Prep Station, housed in the Vanderbilt High‐ Throughput Screening Facility. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH). Dr. Savona receives grants, personal fees and non‐financial support from Astex, Boehringer‐Ingelheim, Celgene Karyopharm, Sunesis, Takeda, TG Therapeutics, Gilead, and Incyte Corporation that are unrelated to this work. Dr. Hiebert receives grants and personal fees from Incyte Corporation that are unrelated to this work. Publisher Copyright: {\textcopyright} 2018 Wiley Periodicals, Inc.",
year = "2019",
month = may,
doi = "10.1002/jcb.28005",
language = "English (US)",
volume = "120",
pages = "7309--7322",
journal = "Journal of supramolecular structure and cellular biochemistry",
issn = "0730-2312",
publisher = "Wiley-Liss Inc.",
number = "5",
}