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| Status |
Public on Dec 02, 2019 |
| Title |
CEBPA Dysfunction Intiates CSF3R Mutant Acute Myeloid Leukemia Through Disruption of Myeloid Lineage Enhancers (ChIP-seq) |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
Acute Myeloid Leukemia (AML) develops due to the acquisition of mutations from multiple functional classes. Here, we demonstrate that activating mutations in the granulocyte colony stimulating factor receptor (CSF3R), cooperate with loss of function mutations in the transcription factor CEBPA to promote acute leukemia development. Terminal myeloid differentiation in response to granulocyte colony-stimulating factor signaling requires wild type CEBPA and is blocked by mutations in CEBPA. Inhibition of the histone demethylase LSD1, restores differentiation and in combination with JAK/STAT blockade, produces significant disease response in vivo. Mutant CEBPA blocks myeloid differentiation by preventing the activation of differentiation-associated enhancers. As enhancer activation precedes promoter activation, CEBPA mutations must occur prior to CSF3R mutations to effectively block differentiation and promote leukemia formation in vivo. This study demonstrates that order-dependent oncogene interaction is a fundamental process in AML. Dissecting this process is critical for understanding disease evolution to enable the development of effective therapeutics.
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| Overall design |
Characterization and comparison of chromatin states across murine hematopoietic cell lines immortalized through retroviral transduction of different combinations of CSF3R and CEBPA mutations: CSF3R.T618I only,CEBPA.v314vw only and CSF3R.T618I+CEBPA.v314vw. Cells transduced with empty vector were used as control. Each treatment group had two replicates.
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| Contributor(s) |
Okhovat M, Braun TP, Maxson JE |
| Citation(s) |
31784538, 32471953 |
| |
| Submission date |
Nov 05, 2018 |
| Last update date |
Jul 02, 2020 |
| Contact name |
Theodore Paul Braun |
| E-mail(s) |
braunt@ohsu.edu
|
| Organization name |
OHSU
|
| Department |
Knight Cancer Institute
|
| Lab |
3181 SW Sam Jackson Park Road
|
| Street address |
3181 SW Sam Jackson Park Road
|
| City |
Portland |
| State/province |
OR |
| ZIP/Postal code |
97239 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
|
| Samples (28)
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| This SubSeries is part of SuperSeries: |
| GSE122166 |
CEBPA Dysfunction Intiates CSF3R Mutant Acute Myeloid Leukemia Through Disruption of Myeloid Lineage Enhancers |
|
| Relations |
| BioProject |
PRJNA503878 |
| SRA |
SRP167880 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE122162_CEBPA.V.merged-H3K27ac-FoldEnrichment.bedGraph.gz |
638.3 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE122162_CEBPA.V.merged-H3K4me1-FoldEnrichment.bedGraph.gz |
990.9 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE122162_CEBPA.V.merged-H3K4me3-FoldEnrichment.bedGraph.gz |
557.8 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE122162_CSF3R.T+CEBPA.V.merged-H3K4me3-FoldEnrichment.bedGraph.gz |
464.2 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE122162_CSF3R.T-CEBPA.V.merged-H3K27ac-FoldEnrichment.bedGraph.gz |
663.7 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE122162_CSF3R.T-CEBPA.V.merged-H3K4me1-FoldEnrichment.bedGraph.gz |
965.8 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE122162_CSF3R.T.merged-H3K27ac-FoldEnrichment.bedGraph.gz |
548.9 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE122162_CSF3R.T.merged-H3K4me1-FoldEnrichment.bedGraph.gz |
893.9 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE122162_CSF3R.T.merged-H3K4me3-FoldEnrichment.bedGraph.gz |
440.4 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE122162_Empty.merged-H3K27ac-FoldEnrichment.bedGraph.gz |
528.8 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE122162_Empty.merged-H3K4me1-FoldEnrichment.bedGraph.gz |
873.5 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE122162_Empty.merged-H3K4me3-FoldEnrichment.bedGraph.gz |
431.9 Mb |
(ftp)(http) |
BEDGRAPH |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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