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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Dec 13, 2019 |
| Title |
All-trans retinoic acid enhances, and a pan-RAR antagonist counteracts, the stem cell promoting activity of EVI1 in acute myeloid leukemia |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Ecotropic virus integration site 1 (EVI1), whose overexpression characterizes a particularly aggressive subtype of acute myeloid leukemia (AML), enhanced anti-leukemic activities of all-trans retinoic acid (atRA) in cell lines and patient samples. However, the drivers of leukemia formation, therapy resistance, and relapse are leukemic stem cells (LSCs), whose properties were hardly reflected in these experimental setups. The present study was designed to address the effects of, and interactions between, EVI1 and retinoids in AML LSCs. We report that Evi1 reduced the maturation of leukemic cells and promoted the abundance, quiescence, and activity of LSCs in an MLL-AF9-driven mouse model of AML. atRA further augmented these effects in an Evi1 dependent manner. EVI1 also strongly enhanced atRA regulated gene transcription in LSC enriched cells. One of their jointly regulated targets, Notch4, was an important mediator of their effects on leukemic stemness. In vitro exposure of leukemic cells to a pan-RAR antagonist caused effects opposite to those of atRA. In vivo antagonist treatment delayed leukemogenesis and reduced LSC abundance, quiescence, and activity in Evi1high AML. Key results were confirmed in human myeloid cell lines retaining some stem cell characteristics as well as in primary human AML samples. In summary, our study is the first to report the importance of EVI1 for key properties of AML LSCs. Furthermore, it shows that atRA enhances, and a pan-RAR antagonist counteracts, the effects of EVI1 on AML stemness, thus raising the possibility of using RAR antagonists in the therapy of EVI1high AML.
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| Overall design |
Gene expression profiles of solvent or atRA-treated Evi1high and Evi1low leukemic stem cell enriched cells (LSCe), in triplicate for Evi1high and duplicate for Evi1low LSCe, using Illumina HiSeq 3000
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| Contributor(s) |
Nguyen CH, Hackl H, Wieser R |
| Citation(s) |
31822659 |
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| Submission date |
Dec 03, 2018 |
| Last update date |
Jan 02, 2020 |
| Contact name |
Rotraud Wieser |
| E-mail(s) |
rotraud.wieser@meduniwien.ac.at
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| Organization name |
Medical University of Vienna
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| Department |
Clinic of Medicine I
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| Street address |
Waehringer Guertel 18-20
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| City |
Vienna |
| ZIP/Postal code |
1090 |
| Country |
Austria |
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| Platforms (1) |
| GPL21493 |
Illumina HiSeq 3000 (Mus musculus) |
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| Samples (10)
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| GSM3498698 |
Spleen LSCe from mice transplanted with shCtrl-transduced LCLSK-MA9 (mouse 1), treated with DMSO |
| GSM3498699 |
Spleen LSCe from mice transplanted with shCtrl-transduced LCLSK-MA9 (mouse 3), treated with DMSO |
| GSM3498700 |
Spleen LSCe from mice transplanted with shCtrl-transduced LCLSK-MA9 (mouse 2), treated with DMSO |
| GSM3498701 |
Spleen LSCe from mice transplanted with shCtrl-transduced LCLSK-MA9 (mouse 2), treated with atRA |
| GSM3498702 |
Spleen LSCe from mice transplanted with shCtrl-transduced LCLSK-MA9 (mouse 3), treated with atRA |
| GSM3498703 |
Spleen LSCe from mice transplanted with shCtrl-transduced LCLSK-MA9 (mouse 1), treated with atRA |
| GSM3498704 |
Spleen LSCe from mice transplanted with shEvi1 (clone #41)-transduced LCLSK-MA9, treated with DMSO |
| GSM3498705 |
Spleen LSCe from mice transplanted with shEvi1 (clone #44)-transduced LCLSK-MA9, treated with DMSO |
| GSM3498706 |
Spleen LSCe from mice transplanted with shEvi1 (clone #44)-transduced LCLSK-MA9, treated with atRA |
| GSM3498707 |
Spleen LSCe from mice transplanted with shEvi1 (clone #41)-transduced LCLSK-MA9, treated with atRA |
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| Relations |
| BioProject |
PRJNA507971 |
| SRA |
SRP172046 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE123255_COUNT_MATRIX.txt.gz |
350.5 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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