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| Status |
Public on Sep 04, 2015 |
| Title |
The ability of PML/RARα to initiate leukemia is associated with markedly increased proliferation of promyelocytes despite minor changes in the transcriptome and epigenome. |
| Organism |
Mus musculus |
| Experiment type |
Methylation profiling by high throughput sequencing
|
| Summary |
Acute Promyelocytic Leukemia is characterized by the accumulation in the blood and bone marrow of promyelocytes. The PML/RARα fusion protein is identified as the primary abnormality implicated in the pathology, and is believed to prevent transcription of genes necessary for normal myeloid development and differentiation. Identifying its targets is critical to comprehend the road to pathogenesis. To understand how PML/RARα, in the absence of secondary lesions, alters gene expression, DNA methylation and proliferation we used a novel experimental and sorting strategy to study normal versus preleukemic promyelocytes in vivo. Expression and methylation profiling analyses were performed on highly purified samples. Surprisingly, despite its ability to initiate leukemia, PML/RARα had overall minor effects on both the transcriptome and epigenome. Important regulators of the myeloid maturation program were not altered but, remarkably, PML/RARα promyelocytes showed strong downregulation of secondary and tertiary granule genes. Subtle changes were also observed on the DNA methylation profile, with PML/RARα predominantly mediating hypomethylation. We performed intersection studies between altered loci and previously described PML/RARα binding sites but found little overlap. Importantly, we show for the first time that PML/RARα on its own increases proliferation, and that this increased proliferation correlates with the ability to initiate leukemia.
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| Overall design |
DNA methylation profiling in CD34(+) early promyelocytes and CD34(-) late promyelocytes cells from PML-RARa transgenic mice vs. control mice.
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| Contributor(s) |
Gaillard C, Kogan S, Figueroa ME |
| Citation(s) |
26088929 |
| Submission date |
Jan 13, 2014 |
| Last update date |
May 15, 2019 |
| Contact name |
Maria Eugenia Figueroa |
| E-mail(s) |
mef162@miami.edu
|
| Organization name |
University of Miiami
|
| Department |
Human Genetics
|
| Lab |
Maria Figueroa
|
| Street address |
1501 NW 10th Ave, BRB 709A, Locator code C227
|
| City |
Miami |
| State/province |
FL |
| ZIP/Postal code |
33136 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (20)
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| Relations |
| BioProject |
PRJNA234436 |
| SRA |
SRP035360 |
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