Data from Repression of Vascular Endothelial Growth Factor Expression by the Runt-Related Transcription Factor 1 in Acute Myeloid Leukemia

Abstract

<div>Abstract<p>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 <i>VEGFA</i> promoter, a core mechanism for VEGFA regulation, has not been fully elucidated. We found a significant (<i>P</i> < 0.0001) inverse correlation between expression of VEGFA and AML1/RUNX1 in a large set of gene expression array data. Strikingly, highest <i>VEGFA</i> levels were demonstrated in AML blasts containing a t(8;21) translocation, which involves the AML1/RUNX1 protein (AML1/ETO). Overexpression of <i>AML1/RUNX1</i> led to downregulation of <i>VEGFA</i> expression, whereas blocking of <i>AML1/RUNX1</i> with siRNAs resulted in increased <i>VEGFA</i> expression. Cotransfection of <i>AML1/RUNX1</i> and VEGFA promoter luciferase promoter constructs resulted in a decrease in <i>VEGFA</i> promoter activity. ChIP analysis shows a direct binding of AML1/RUNX1 to the promoter of <i>VEGFA</i> on three AML1/RUNX1 binding sites. Silencing of <i>AML1/ETO</i> caused a decrease in <i>VEGFA</i> 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. <i>Cancer Res; 71(7); 2761–71. ©2011 AACR</i>.</p></div>