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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Jun 23, 2016 |
| Title |
Expression profiling of murine leukemia stem cell (LSC) lines established ex vivo by coexpression of R882H-mutated DNMT3A and NRAS-G12D post treatment with Dot1l inhibitor (Microarray) |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies; however, the underlying oncogenic mechanisms remain elusive. Here, we report that DNMT3A mutational ‘hotspot’ at Arg882 (DNMT3A-R882H) cooperates with constitutively activated RAS in transforming murine hematopoietic stem/progenitor cells (HSPCs) ex vivo and inducing acute leukemias in vivo. DNMT3A-R882H potentiates aberrant transactivation of ‘stemness’ gene expression programs, notably transcription factors Meis1, Hox-A, Mn1 and Mycn. Mechanistically, R882-mutated DNMT3A directly binds to cis-regulatory elements of these genes and induces focal CpG hypomethylation reminiscent of what was seen in human leukemias bearing DNMT3A R882 mutation. Furthermore, DNMT3A-R882H induced DNA hypomethylation facilitates gene enhancer/promoter activation and recruitment of Dot1l-associated transcription elongation machineries. Inactivation of Dot1l represses DNMT3AR882H-mediated stem cell gene dysregulation and acute leukemogenicity.
In this dataset, we provided gene expression profiling data for (1) RH-RAS leukemia stem cells (RH-RAS LSCs), (2) LSCs transformed by MLL-AF9, (3) LSCs transformed by NUP98-JARID1A, and (4) Dot1l inhibitor-treated RH-RAS LSCs.
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| Overall design |
Gene expression data were generated using Mouse Genome 430 2.0 Microarray (Affymetrix) for four independently derived RH-RAS LSC lines (termed as LSC RH-RAS #1, #2, #3 and #4), two RH-RAS LSC lines (LSC RH-RAS #1 and # 3) treated with 1 µM SGC0946 (a Dot1l-specific small-molecule inhibitor) for 4 days, one MLL-AF9-transformed progenitor line and three NUP98-JARID1A transformed progenitor lines.
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| Contributor(s) |
Lu R, Wang GG |
| Citation(s) |
27344947 |
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| Submission date |
Jul 28, 2015 |
| Last update date |
Feb 11, 2019 |
| Contact name |
Rui Lu |
| E-mail(s) |
[email protected]
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| Organization name |
Univ of Alabama at Birmingham
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| Street address |
1824 6th Ave S
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| City |
Birmingham |
| State/province |
AL |
| ZIP/Postal code |
35294 |
| Country |
USA |
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| Platforms (1) |
| GPL1261 |
[Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array |
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| Samples (10)
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| This SubSeries is part of SuperSeries: |
| GSE71475 |
Epigenetic perturbations by Arg882-mutated DNMT3A potentiate aberrant stem cell gene expression program and acute leukemia development |
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| Relations |
| BioProject |
PRJNA291209 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE71439_RAW.tar |
36.6 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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