GEO Logo
   NCBI > GEO > Accession DisplayHelp Not logged in | LoginHelp
GEO help: Mouse over screen elements for information.
Series GSE63782 Query DataSets for GSE63782
Status Public on Sep 08, 2015
Title Transcriptional plasticity promotes primary and acquired resistance to BET bromodomain inhibition
Organisms Homo sapiens; Mus musculus
Experiment type Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Summary Following the discovery of BRD4 as a non-oncogene addiction target in acute myeloid leukemia (AML), BET inhibitors are being explored as promising therapeutic avenue in numerous cancers. While clinical trials have reported single-agent activity in advanced hematologic malignancies, mechanisms determining the response to BET inhibition remain poorly understood. To identify factors involved in primary and acquired BET resistance in leukemia, we performed a chromatin-focused shRNAmir screen in a sensitive MLL/AF9; NrasG12D‑driven AML model, and investigated dynamic transcriptional profiles in sensitive and resistant murine and human leukemias. Our screen reveals that suppression of the PRC2 complex, contrary to effects in other contexts, promotes BET resistance in AML. PRC2 suppression does not directly affect the regulation of Brd4-dependent transcripts, but facilitates the remodeling of regulatory pathways that restore the transcription of key targets such as Myc. Similarly, while BET inhibition triggers acute MYC repression in human leukemias regardless of their sensitivity, resistant leukemias are uniformly characterized by their ability to rapidly restore MYC transcription. This process involves the activation and recruitment of WNT signaling components, which compensate for the loss of BRD4 and drive resistance in various cancer models. Dynamic ChIP- and STARR-seq enhancer profiles reveal that BET-resistant states are characterized by remodeled regulatory landscapes, involving the activation of a focal MYC enhancer that recruits WNT machinery in response to BET inhibition. Together, our results identify and validate WNT signaling as a driver and candidate biomarker of primary and acquired BET resistance in leukemia, and implicate the rewiring of transcriptional programs as an important mechanism promoting resistance to BET inhibitors and, potentially, other chromatin-targeted therapies.
Overall design RNA-Seq of DMSO- or JQ1-treated cancer cell lines; ChIP-seq for H3K36me3 and H3K27me3 in a leukemia cell line treated either with DMSO or JQ1, ChIP-seq for H3K27ac in resistant and sensitive mouse and human leukemia. Functional enhancer mapping (STARR-seq) in K-562 treated either with DMSO or JQ1.
Contributor(s) Rathert P, Neumann T, Muhar M, Zuber J, Muerdter F, Stark A, Roe J, Vakoc C
Citation(s) 26367798
Submission date Dec 02, 2014
Last update date May 15, 2019
Contact name Philipp Rathert
Organization name University Stuttgart
Department Biochemistry
Street address Allmandring 31
City Stuttgart
State/province Germany
ZIP/Postal code 70569
Country Germany
Platforms (6)
GPL11154 Illumina HiSeq 2000 (Homo sapiens)
GPL13112 Illumina HiSeq 2000 (Mus musculus)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
Samples (103)
GSM1557034 RN2 Ren.713 DMSO
GSM1557035 RN2 Ren.713 2h JQ1 200 nM
GSM1557036 RN2 Ren.713 24h JQ1 200 nM
BioProject PRJNA269063
SRA SRP050440

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE63782_BRD_KD_RPKMs.tsv.gz 1.2 Mb (ftp)(http) TSV
GSE63782_BRD_KD_counts.tsv.gz 323.2 Kb (ftp)(http) TSV
GSE63782_RAW.tar 3.8 Gb (http)(custom) TAR (of BW)
GSE63782_human_JQ1_timeseries_RPKMs.tsv.gz 8.1 Mb (ftp)(http) TSV
GSE63782_human_JQ1_timeseries_counts.tsv.gz 1.7 Mb (ftp)(http) TSV
GSE63782_mouse_KD_RPKMs.tsv.gz 2.6 Mb (ftp)(http) TSV
GSE63782_mouse_KD_counts.tsv.gz 641.3 Kb (ftp)(http) TSV
GSE63782_refseq.hg19.2014_0110.imp.merged.TSS.bed.gz 292.8 Kb (ftp)(http) BED
GSE63782_refseq.hg19.2014_0110.imp.merged.uniq.exons.fulltable.gtf.gz 2.1 Mb (ftp)(http) GTF
GSE63782_refseq.mm10.2014_3006.imp.merged.TSS.bed.gz 290.4 Kb (ftp)(http) BED
GSE63782_refseq.mm10.2014_3006.imp.merged.uniq.exons.fulltable.gtf.gz 2.0 Mb (ftp)(http) GTF
SRA Run SelectorHelp
Raw data are available in SRA
Processed data are available on Series record
Processed data provided as supplementary file

| NLM | NIH | GEO Help | Disclaimer | Accessibility |
NCBI Home NCBI Search NCBI SiteMap