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| 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.
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| 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.
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| 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 |
| E-mail(s) |
philipp.rathert@ibtb.uni-stuttgart.de
|
| Organization name |
University Stuttgart
|
| Department |
Biochemistry
|
| Street address |
Allmandring 31
|
| City |
Stuttgart |
| State/province |
Germany |
| ZIP/Postal code |
70569 |
| Country |
Germany |
| |
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| Platforms (6)
|
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
| GPL18460 |
Illumina HiSeq 1500 (Homo sapiens) |
| GPL18480 |
Illumina HiSeq 1500 (Mus musculus) |
|
| Samples (103)
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|
| Relations |
| BioProject |
PRJNA269063 |
| SRA |
SRP050440 |
| 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 Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
| Processed data provided as supplementary file |
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