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Cell Rep. 2014 Sep 25;8(6):1919-1929. doi: 10.1016/j.celrep.2014.08.025. Epub 2014 Sep 18.

Inducible in vivo silencing of Brd4 identifies potential toxicities of sustained BET protein inhibition.

Author information

1
Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
2
Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Watson School of Biological Sciences, Cold Spring Harbor, NY 11724, USA; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
3
Hubrecht Institute/KNAW, Uppsalalaan 8, Utrecht 3584 CT, the Netherlands.
4
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
5
Hubrecht Institute/KNAW, Uppsalalaan 8, Utrecht 3584 CT, the Netherlands; University Medical Center Utrecht, Uppsalalaan 8, Utrecht 3584 CT, the Netherlands.
6
Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, New York, NY 10065, USA. Electronic address: lowes@mskcc.org.

Abstract

BET family proteins are novel therapeutic targets for cancer and inflammation and represent the first chromatin readers against which small-molecule inhibitors have been developed. First-generation BET inhibitors have shown therapeutic efficacy in preclinical models, but the consequences of sustained BET protein inhibition in normal tissues remain poorly characterized. Using an inducible and reversible transgenic RNAi mouse model, we show that strong suppression of the BET protein Brd4 in adult animals has dramatic effects in multiple tissues. Brd4-depleted mice display reversible epidermal hyperplasia, alopecia, and decreased cellular diversity and stem cell depletion in the small intestine. Furthermore, Brd4-suppressed intestines are sensitive to organ stress and show impaired regeneration following irradiation, suggesting that concurrent Brd4 suppression and certain cytotoxic therapies may induce undesirable synergistic effects. These findings provide important insight into Brd4 function in normal tissues and, importantly, predict several potential outcomes associated with potent and sustained BET protein inhibition.

PMID:
25242322
PMCID:
PMC4234106
DOI:
10.1016/j.celrep.2014.08.025
[Indexed for MEDLINE]
Free PMC Article

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