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BRD4 profiling identifies critical Chronic Lymphocytic Leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct BET inhibitor [expression profiling]

ABSTRACT: BRD4 profiling identifies critical Chronic Lymphocytic Leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct BET inhibitor [expression profiling]

PROVIDER: PRJNA431429 | ENA |

REPOSITORIES: ENA

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BRD4 profiling identifies critical Chronic Lymphocytic Leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct BET inhibitor [expression profiling]

2018-04-17 | GSE109587 | GEO

BRD4 profiling identifies critical Chronic Lymphocytic Leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct BET inhibitor [ChIP-seq]

2018-04-17 | GSE109411 | GEO

BRD4 profiling identifies critical Chronic Lymphocytic Leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct BET inhibitor

Project description:BRD4 profiling identifies critical Chronic Lymphocytic Leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct BET inhibitor

| PRJNA431438 | ENA

BRD4 profiling identifies critical Chronic Lymphocytic Leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct BET inhibitor [ChIP-seq]

Project description:BRD4 profiling identifies critical Chronic Lymphocytic Leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct BET inhibitor [ChIP-seq]

| PRJNA430819 | ENA

BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor.

Project description:Bromodomain and extra-terminal (BET) family proteins are key regulators of gene expression in cancer. Herein, we utilize BRD4 profiling to identify critical pathways involved in pathogenesis of chronic lymphocytic leukemia (CLL). BRD4 is overexpressed in CLL and is enriched proximal to genes upregulated or de novo expressed in CLL with known functions in disease pathogenesis and progression. These genes, including key members of the B-cell receptor (BCR) signaling pathway, provide a rationale for this therapeutic approach to identify new targets in alternative types of cancer. Additionally, we describe PLX51107, a structurally distinct BET inhibitor with novel in vitro and in vivo pharmacologic properties that emulates or exceeds the efficacy of BCR signaling agents in preclinical models of CLL. Herein, the discovery of the involvement of BRD4 in the core CLL transcriptional program provides a compelling rationale for clinical investigation of PLX51107 as epigenetic therapy in CLL and application of BRD4 profiling in other cancers.Significance: To date, functional studies of BRD4 in CLL are lacking. Through integrated genomic, functional, and pharmacologic analyses, we uncover the existence of BRD4-regulated core CLL transcriptional programs and present preclinical proof-of-concept studies validating BET inhibition as an epigenetic approach to target BCR signaling in CLL. Cancer Discov; 8(4); 458-77. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 371.

| S-EPMC5882533 | biostudies-literature

BRD4 profiling identifies critical Chronic Lymphocytic Leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct BET inhibitor

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-04-17 | GSE109593 | GEO

Transcriptome analysis of dominant-negative Brd4 mutants identifies Brd4-specific target genes of BET inhibitor JQ1

Project description:We analyzed anti-proliferative dominant-negative Brd4 mutants that compete with the function of distinct Brd4 domains. We used these Brd4 mutants to compare the Brd4-specific transcriptome with the transcriptome of JQ1 treated cells.

2017-06-09 | GSE92456 | GEO

BRD4 degradation via stabilization of a native interaction with DCAF16

Project description:Targeted protein degradation is a modality based on small molecules that induce proximity between a protein of interest (POI) and an E3 ubiquitin ligase, thus prompting POI ubiquitination and degradation. To expand the reach of TPD, current research is geared to unlock novel E3s. To that end, the transcriptional co-activator protein BRD4 has emerged as a frequently used POI. Derivatization of known BRD4 ligands with structurally diverse substituents has yielded a suite of potent BRD4 degraders, thus generating the notion that BRD4 is particularly amenable to TPD. Here, we mechanistically characterize two BRD4 degraders via orthogonal CRISPR screens. Despite their structural dissimilarity, both degraders functionally converge on a unifying mechanism of action that involves the CRL4DCAF16 ligase complex. Using recombinant reconstitution, as well as biophysical and structural elucidation, we demonstrate that BRD4 has an intrinsic activity for DCAF16, which is further enhanced by both compounds. We uncover a novel mode of molecular recognition based on multivalent "gluing" of BRD4 onto DCAF16 that requires both bromodomains of BRD4. Our data thus imply a substantial conceptual overlap between PROTACs and molecular glue degraders, and highlight multivalency as a novel concept in the design of proximity-inducing drugs.

2024-01-08 | PXD040570 | Pride

Hematopoietic transcription factors and p300/CBP shape the effects of BET bromodomain inhibition in leukemia [ChIP-Seq]

Project description:The bromodomain and extraterminal (BET) protein Brd4 is a validated drug target in leukemia, yet its regulatory function in this disease is not well understood. Here, we show that Brd4 chromatin occupancy in acute myeloid leukemia closely correlates with the hematopoietic transcription factors (TFs) Pu.1, Fli1, Erg, C/EBPα, C/EBPβ, and Myb at nucleosome-depleted enhancer and promoter regions. We provide evidence that these TFs, in conjunction with the lysine acetyltransferase activity of p300/CBP, facilitate Brd4 recruitment to their occupied sites to promote transcriptional activation. Moreover, chemical inhibition of BET bromodomains is found to suppress the functional output each hematopoietic TF, thereby interfering with essential lineage-specific transcriptional circuits in this disease. These findings reveal a chromatin-based signaling cascade comprised of hematopoietic TFs, p300/CBP, and Brd4, which supports leukemia maintenance and is suppressed by BET bromodomain inhibition. ChIP-Seq for regulatory factors of Brd4 in MLL-AF9 transformed acute myeloid leukemia cells (RN2)

2015-05-01 | E-GEOD-66122 | biostudies-arrayexpress

Enhancer profiling of chronic lymphocytic leukemia cells

Project description:Enhancer profiling has emerged as a powerful approach for discovering the cis-regulatory elements that define transcriptional core regulatory circuits. Characteristic biochemical and biophysical attributes of chromatin mark active enhancer elements, which can be leveraged with genome-wide assay technologies for discovery. This includes chromatin immunoprecipitation followed by sequencing (ChIP-seq) for histone H3 acetylated lysine 27 (H3K27ac). Enhancers are also characterized by regions of open chromatin, hypersensitive to digestion by transposases measurable by the assay for transposase-accessible chromatin (ATAC-seq). By integrating measures of chromatin accessibility and domains of enriched H3K27 acetylation, we have generated enhancer landscapes from chronic lymphocytic leukemia (CLL) representative cell lines including MEC1, MEC2, OSU-CLL, and CII. Targeting enhancer signaling via BET bromodomain inhibition (using the inhibitor JQ1) disrupts enhancer-dependent gene expression as measured with RNA-sequencing in CLL cell lines.

2018-11-29 | GSE119744 | GEO

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