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| Status |
Public on Oct 01, 2023 |
| Title |
Acute resistance to BET inhibitors remodels compensatory transcriptional programmes via p300 co-activation |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Aiming to discover anticipatory combination treatments for better and longer disease response rates, we here explore immediate epigenetic and transcriptional reactions after BET inhibition. BET inhibitor-driven decommissioning of BRD4 from chromatin is followed by an acute compensatory feedback loop intended to attenuate the loss of transcription. Critically, this adaptation occurs almost exclusively at key AML maintenance genes and is co-mediated by p300. However, this also provides a rationale therapeutic opportunity, with BET- followed by p300 inhibition. Of note, the transcriptional programs that p300 regulates to induce resistance to BET inhibition differ between AML subtypes. In some AMLs, p300 regulates transitional transcriptional patterns that allow homeostatic adjustments during earlier stages of resistance to BET inhibition, so that the importance of p300 is highest during initial resistance stages. In other AMLs, p300 leads to a linear induction of resistance to BET inhibition and, therefore, remains crucial throughout all stages of acquisition of resistance.
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| Overall design |
Integrative analysis of ChIP Seq, nucRNA Seq and ATAC-Seq in DMSO- and BETi-treated KASUMI-1 cell. Mechanism validation in SKNO1 and OCI-AML3 cells. RNASeq of DMSO-, BETi- and p300i-treated AML cell lines. Longitudinal gene expression quantitation via RNASeq and response to p300i during the process of BETi-resistance in SKNO1 and OCI-AML3 cells.
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| Contributor(s) |
Sasca D, Huntly B |
| Citation missing |
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| |
| Submission date |
Feb 21, 2021 |
| Last update date |
Oct 01, 2023 |
| Contact name |
Daniel Sasca |
| E-mail(s) |
danielsasca@gmail.com
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| Organization name |
University Medical Center Mainz
|
| Department |
Department of Hematology and Oncology
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| Street address |
Langenbeckstr 1
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| City |
Mainz |
| ZIP/Postal code |
55131 |
| Country |
Germany |
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| Platforms (2) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (118)
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| Relations |
| BioProject |
PRJNA703540 |
| SRA |
SRP307352 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE167163_BETi1_KASUMI_nucRNASeq.bedgraph.gz |
313.1 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_BETi2_KASUMI_nucRNASeq.bedgraph.gz |
174.1 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_BETi_1_KASUMI_ATACSeq.bedgraph.gz |
310.9 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_BETi_2_KASUMI_ATACSeq.bedgraph.gz |
230.3 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_BRD4_BETi_KASUMI_ChIPSeq.bedgraph.gz |
65.0 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_BRD4_DMSO_KASUMI_ChIPSeq.bedgraph.gz |
74.8 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_CDK9_BETi_KASUMI_ChIPSeq.bedgraph.gz |
259.5 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_CDK9_DMSO_KASUMI_ChIPSeq.bedgraph.gz |
197.6 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_DMSO1_KASUMI_nucRNASeq.bedgraph.gz |
172.6 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_DMSO2_KASUMI_nucRNASeq.bedgraph.gz |
156.4 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_DMSO_1_KASUMI_ATACSeq.bedgraph.gz |
258.7 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_DMSO_2_KASUMI_ATACSeq.bedgraph.gz |
248.0 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_ERG_BETi_KASUMI_ChIPSeq.bedgraph.gz |
174.4 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_ERG_DMSO_KASUMI_ChIPSeq.bedgraph.gz |
243.3 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_FLI1_BETi_KASUMI_ChIPSeq.bedgraph.gz |
190.0 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_FLI1_DMSO_KASUMI_ChIPSeq.bedgraph.gz |
205.7 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_H3K27ac_BETi_KASUMI_ChIPSeq.bedgraph.gz |
337.6 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_H3K27ac_DMSO_KASUMI_ChIPSeq.bedgraph.gz |
334.9 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_Input_BETi_KASUMI_ChIPSeq.bedgraph.gz |
240.1 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_Input_DMSO_KASUMI_ChIPSeq.bedgraph.gz |
381.1 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_KASUMI_RNASeq_DMSO_vs_BETi_counts.txt.gz |
370.1 Kb |
(ftp)(http) |
TXT |
| GSE167163_LMO2_BETi_KASUMI_ChIPSeq.bedgraph.gz |
211.3 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_LMO2_DMSO_KASUMI_ChIPSeq.bedgraph.gz |
154.2 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_MOLM13_RNASeq_DMSO_vs_BETi_counts.txt.gz |
397.3 Kb |
(ftp)(http) |
TXT |
| GSE167163_PU.1_BETi_KASUMI_ChIPSeq.bedgraph.gz |
136.1 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_PU.1_DMSO_KASUMI_ChIPSeq.bedgraph.gz |
112.4 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_RAW.tar |
2.7 Gb |
(http)(custom) |
TAR (of BEDGRAPH) |
| GSE167163_RUNX1-ETO_BETi_KASUMI_ChIPSeq.bedgraph.gz |
75.3 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_RUNX1-ETO_DMSO_KASUMI_ChIPSeq.bedgraph.gz |
58.3 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_RUNX1_BETi_KASUMI_ChIPSeq.bedgraph.gz |
97.3 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_RUNX1_DMSO_KASUMI_ChIPSeq.bedgraph.gz |
92.4 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_Readcounts_all_DMSO_vs_p300i_RNASeq_comparisons.txt.gz |
1.3 Mb |
(ftp)(http) |
TXT |
| GSE167163_SKNO1_counts_all_comparisons.txt.gz |
1.2 Mb |
(ftp)(http) |
TXT |
| GSE167163_p300_BETi_KASUMI_ChIPSeq.bedgraph.gz |
239.1 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE167163_p300_DMSO_KASUMI_ChIPSeq.bedgraph.gz |
241.5 Mb |
(ftp)(http) |
BEDGRAPH |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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