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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Jul 30, 2019 |
| Title |
The p30 isoform of CEBPA uncovers a silent enhancer to drive the expression of the tumor promotive factor CD73 in CEBPA mutant AML |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
CEBPA is a key hematopoietic transcription factor (TF), found mutated in 5-14% of all acute myeloid leukemia (AML) cases, but the direct molecular ramifications of this driver mutation remains elusive. To investigate CEBPA-mutant AML, we compared patient aberrant genetic programs with changes in a precise mouse model (Lp30) expressing only the cancer-prevalent truncated CEBPA, p30, and identified a stringent cross-species AML program. Small-scale ChIP-seq methodology revealed aberrantly activated enhancers, exclusively occupied by CEBPA in leukemia. One cancer-enhancer upstream of Nt5e, encoding CD73, was physically and functionally linked to this conserved AML gene, and could be activated by CEBPA. Targeting of CD73-adenosine signaling increased survival in AML transplanted mice. Our data thus indicate a first-in-class link between a TF cancer driver mutation and a druggable, direct transcriptional target.
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| Overall design |
RNA-seq of samples of human healthy donors vs CEBPA-biallelic AML patients was compared to RNA-seq of mouse WT versus CEBPA-biallelic AML model Lp30. ChIP-seq of CEBPA, Histone marks H3K27ac and H3K4me1 in mouse WT versus CEBPA-biallelic AML model Lp30. ChIP-seq of histone mark H3K27ac in samples of human healthy donors versus mono-allelic and biallelic CEBPA-mut AML. All samples are rigorously FACS isolated GMP phenotypic cells, in vivo material. RNA-seq, different shRNA constructs, Nt5e-KD versus scramble-KD in mouse Lp30 CEBPA-biallelic model cells in tissue culture.
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| Contributor(s) |
Jakobsen JS, Laursen LG, Schuster MB, Pundhir S, Rapin N, Schoof E, Ge Y, Vitting-Seerup K, Gentil C, Jendholm J, Hokland P, Fitzgibbon J, Porse BT |
| Citation(s) |
31309149, 37794021 |
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| Submission date |
Aug 23, 2018 |
| Last update date |
Oct 18, 2023 |
| Contact name |
Janus Schou Jakobsen |
| Organization name |
University of Copenhagen
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| Department |
BRIC
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| Lab |
Bo Porse laboratory
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| Street address |
Ole Maaløes Vej 5
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| City |
Copenhagen N |
| ZIP/Postal code |
2200 |
| Country |
Denmark |
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| Platforms (3) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (35)
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| Relations |
| BioProject |
PRJNA487543 |
| SRA |
SRP158679 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE118963_Nt5e_KD_read_counts.xlsx |
5.3 Mb |
(ftp)(http) |
XLSX |
| GSE118963_RAW.tar |
3.7 Gb |
(http)(custom) |
TAR (of BW) |
| GSE118963_p30_p42_common_coord_mm9.xlsx |
878.4 Kb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
| Processed data are available on Series record |
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