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

Cancer Cell
Authors
Keywords
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.

Year of Publication
2018
Journal
Cancer Cell
Volume
34
Issue
6
Pages
982-995.e7
Date Published
2018 Dec 10
ISSN
1878-3686
DOI
10.1016/j.ccell.2018.11.001
PubMed ID
30503705
PubMed Central ID
PMC6298230
Links
Grant list
R01 GM107427 / GM / NIGMS NIH HHS / United States
R01 CA193910 / CA / NCI NIH HHS / United States
R01 CA213442 / CA / NCI NIH HHS / United States
P01 CA081534 / CA / NCI NIH HHS / United States
P30 CA016058 / CA / NCI NIH HHS / United States
K99 CA190861 / CA / NCI NIH HHS / United States
R00 CA190861 / CA / NCI NIH HHS / United States