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.
Highlights
In cancer, including hematological malignancies, VEGFA is considered as one of the most important regulators of tumorassociated angiogenesis [1,2,3]
We identified wild-type AML1/RUNX1 as an important transcriptional repressor of VEGFA mRNA expression in acute myeloid leukemia (AML) cells, whereas repression of VEGFA mRNA expression is attenuated by AML1/RUNX1 mutations, such as in AML1/ETO-positive AML blasts
To investigate the relationship between VEGFA expression and RUNX1 expression A highly significant inverse correlation was found between VEGFA and AML1/RUNX1 mRNA expression (n 1⁄4 525, rho 1⁄4 À0.173, P 1⁄4 < 0.0001; Fig. 1)
Summary
In cancer, including hematological malignancies, VEGFA is considered as one of the most important regulators of tumorassociated angiogenesis [1,2,3]. Besides its role in angiogenesis, VEGFA has been shown to enhance leukemic cell survival and/or leukemic cell growth through an autocrine loop, and a paracrine pathway in which VEGFA stimulates the production of hematopoietic growth factors by endothelial cells and/or stromal cells [4,5,6,7]. AML-derived VEGFA is an independent adverse prognostic factor related to worse treat-. Authors' Affiliations: 1Division of Pediatric Oncology, Department of Pediatrics, Beatrix Children's Hospital and 2Division of Hematology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
