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Cancer Cell. 2018 Dec 10;34(6):982-995.e7. doi: 10.1016/j.ccell.2018.11.001. Epub 2018 Nov 29.

Enhancer Architecture and Essential Core Regulatory Circuitry of Chronic Lymphocytic Leukemia.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA; Massachusetts General Hospital Cancer Center, Harvard Medical School, 149 13th St. Charlestown, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT & Harvard, Cambridge, MA 02142, USA. Electronic address: christopher.ott@mgh.harvard.edu.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA; Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA.
3
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA; Massachusetts General Hospital Cancer Center, Harvard Medical School, 149 13th St. Charlestown, Boston, MA 02129, USA.
4
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA.
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA; Medical School, Xiamen University, Xiamen 361102, China.
6
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Electronic address: jennifer_brown@dfci.harvard.edu.
7
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT & Harvard, Cambridge, MA 02142, USA; Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: james.bradner@novartis.com.

Abstract

Enhancer profiling is a powerful approach for discovering cis-regulatory elements that define the core transcriptional regulatory circuits of normal and malignant cells. Gene control through enhancer activity is often dominated by a subset of lineage-specific transcription factors. By integrating measures of chromatin accessibility and enrichment for H3K27 acetylation, we have generated regulatory landscapes of chronic lymphocytic leukemia (CLL) samples and representative cell lines. With super enhancer-based modeling of regulatory circuits and assessments of transcription factor dependencies, we discover that the essential super enhancer factor PAX5 dominates CLL regulatory nodes and is essential for CLL cell survival. Targeting enhancer signaling via BET bromodomain inhibition disrupts super enhancer-dependent gene expression with selective effects on CLL core regulatory circuitry, conferring potent anti-tumor activity.

KEYWORDS:

BET bromodomain inhibitor; PAX5; chronic lymphocytic leukemia; enhancers

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PMID:
30503705
PMCID:
PMC6298230
[Available on 2019-12-10]
DOI:
10.1016/j.ccell.2018.11.001

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