RESUMEN

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.

Asunto(s)

Cromatina/genética , Elementos de Facilitación Genéticos/genética , Regulación Leucémica de la Expresión Génica/genética , Leucemia Linfocítica Crónica de Células B/genética , Acetilación , Animales , Azepinas/farmacología , Línea Celular Tumoral , Cromatina/efectos de los fármacos , Cromatina/metabolismo , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Histonas/metabolismo , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/metabolismo , Ratones Noqueados , Factor de Transcripción PAX5/genética , Factor de Transcripción PAX5/metabolismo , Unión Proteica , Proteínas/antagonistas & inhibidores , Proteínas/genética , Proteínas/metabolismo , Triazoles/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos