Enhancer Architecture and Essential Core Regulatory Circuitry of Chronic Lymphocytic Leukemia

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. [Display omitted] •Histone acetylation and chromatin accessibility reveal enhancer signatures of CLL•Super enhancers mediate the CLL transcription factor core regulatory circuitry•PAX5 is a core regulator of CLL super enhancers essential for CLL cell survival•BET inhibition effectively disrupts CLL super enhancer circuits Analyzing integrative enhancer profiles and transcription factor dependencies, Ott et al. construct enhancer-based core regulatory circuits of chronic lymphocytic leukemia (CLL) and reveal a dominant and essential role for PAX5. BET inhibition disrupts CLL super enhancer networks and suppresses CLL growth.