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Repression of vascular endothelial growth factor expression by the runt-related transcription factor 1 in acute myeloid leukemia.

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.
AuthorsArja 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
JournalCancer research (Cancer Res) Vol. 71 Issue 7 Pg. 2761-71 (Apr 01 2011) ISSN: 1538-7445 [Electronic] United States
PMID21447743 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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
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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