Abstract |
VEGFA is considered one of the most important regulators of tumor-associated angiogenesis in cancer. In acute myeloid leukemia (AML) VEGFA is an independent prognostic factor for reduced overall and relapse-free survival. Transcriptional activation of the VEGFA promoter, a core mechanism for VEGFA regulation, has not been fully elucidated. We found a significant (P < 0.0001) inverse correlation between expression of VEGFA and AML1/RUNX1 in a large set of gene expression array data. Strikingly, highest VEGFA levels were demonstrated in AML blasts containing a t(8;21) translocation, which involves the AML1/ RUNX1 protein (AML1/ETO). Overexpression of AML1/RUNX1 led to downregulation of VEGFA expression, whereas blocking of AML1/RUNX1 with siRNAs resulted in increased VEGFA expression. Cotransfection of AML1/RUNX1 and VEGFA promoter luciferase promoter constructs resulted in a decrease in VEGFA promoter activity. ChIP analysis shows a direct binding of AML1/RUNX1 to the promoter of VEGFA on three AML1/RUNX1 binding sites. Silencing of AML1/ETO caused a decrease in VEGFA mRNA expression and a decrease in secreted VEGFA protein levels in AML1/ETO-positive Kasumi-1 cells. Taken together, these data pinpoint to a model whereby in normal cells AML1/RUNX1 acts as a repressor for VEGFA, while in AML cells VEGFA expression is upregulated due to AML1/RUNX1 aberrations, for example, AML1/ETO. In conclusion, these observations give insight in the regulation of VEGFA at the mRNA level in AML.
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Authors | Arja Ter Elst, Bin Ma, Frank J G Scherpen, Hendrik J M de Jonge, Jenny Douwes, Albertus T J Wierenga, Jan Jacob Schuringa, Willem A Kamps, Eveline S J M de Bont |
Journal | Cancer research
(Cancer Res)
Vol. 71
Issue 7
Pg. 2761-71
(Apr 01 2011)
ISSN: 1538-7445 [Electronic] United States |
PMID | 21447743
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Core Binding Factor Alpha 2 Subunit
- Proto-Oncogene Proteins
- RNA, Messenger
- RUNX1 Translocation Partner 1 Protein
- RUNX1 protein, human
- RUNX1T1 protein, human
- Transcription Factors
- VEGFA protein, human
- Vascular Endothelial Growth Factor A
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Topics |
- Binding Sites
- Cell Line, Tumor
- Chromosomes, Human, Pair 21
- Chromosomes, Human, Pair 8
- Core Binding Factor Alpha 2 Subunit
(biosynthesis, genetics)
- Down-Regulation
- Gene Expression Regulation, Neoplastic
- Gene Knockdown Techniques
- Gene Silencing
- HL-60 Cells
- Humans
- Leukemia, Myeloid, Acute
(genetics, metabolism)
- Mutation
- Promoter Regions, Genetic
- Proto-Oncogene Proteins
(biosynthesis, genetics)
- RNA, Messenger
(biosynthesis, genetics)
- RUNX1 Translocation Partner 1 Protein
- Transcription Factors
(biosynthesis, genetics)
- Transcription, Genetic
- Translocation, Genetic
- Up-Regulation
- Vascular Endothelial Growth Factor A
(antagonists & inhibitors, biosynthesis, genetics)
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