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

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.

• Publication year

  2011

• Venue

  Cancer Research

• Publication date

  2011-04-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1158/0008-5472.CAN-10-0402PMID 21447743
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Vascular endothelial growth factor activation of endothelial cells is mediated by early growth response-3.

  2010influential reference
• Molecular pathways mediating MDS/AML with focus on AML1/RUNX1 point mutations

  2009cited by this paper
• AML at older age: age-related gene expression profiles reveal a paradoxical down-regulation of p16INK4A mRNA with prognostic significance.

  2009cited by this paper
• Gene expression profiling of minimally differentiated acute myeloid leukemia: M0 is a distinct entity subdivided by RUNX1 mutation status.

  2009cited by this paper
• HDAC4 Represses Vascular Endothelial Growth Factor Expression in Chondrosarcoma by Modulating RUNX2 Activity*

  2009cited by this paper
• AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations.

  2009cited by this paper
• Gene expression profiling of minimally differentiated acute myeloid leukemia : M 0 is a distinct entity subdivided by RUNX 1 mutation status

  2009cited by this paper
• Growth inhibition of AML cells with specific chromosome abnormalities by monoclonal antibodies to receptors for vascular endothelial growth factor.

  2009cited by this paper
• t(8;21) acute myeloid leukaemia cells are dependent on vascular endothelial growth factor (VEGF)/VEGF receptor type2 pathway and phosphorylation of Akt

  2006cited by this paper
• RUNX3 Inhibits the Expression of Vascular Endothelial Growth Factor and Reduces the Angiogenesis, Growth, and Metastasis of Human Gastric Cancer

  2006cited by this paper
• Disease-specific expression of VEGF and its receptors in AML cells: possible autocrine pathway of VEGF/type1 receptor of VEGF in t(15;17) AML and VEGF/type2 receptor of VEGF in t(8;21) AML

  2006cited by this paper
• The t(8;21) translocation converts AML1 into a constitutive transcriptional repressor

  2005cited by this paper
• Impaired intranuclear trafficking of Runx2 (AML3/CBFA1) transcription factors in breast cancer cells inhibits osteolysis in vivo.

  2005cited by this paper
• The runx genes: gain or loss of function in cancer

  2005cited by this paper
• Role of RUNX family members in transcriptional repression and gene silencing

  2004influential reference
• Point mutations in the RUNX1/AML1 gene: another actor in RUNX leukemia

  2004cited by this paper
• Internal and external autocrine VEGF/KDR loops regulate survival of subsets of acute leukemia through distinct signaling pathways.

  2004cited by this paper
• Haploinsufficiency of AML1 results in a decrease in the number of LTR-HSCs while simultaneously inducing an increase in more mature progenitors.

  2004cited by this paper
• Prognostically useful gene-expression profiles in acute myeloid leukemia.

  2004cited by this paper
• AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis

  2004cited by this paper
• Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway

  2003cited by this paper
• Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis

  2003cited by this paper
• AML1/RUNX1 mutations are infrequent, but related to AML‐M0, acquired trisomy 21, and leukemic transformation in pediatric hematologic malignancies

  2003cited by this paper
• Vascular Endothelial Growth Factor–Regulated Gene Expression in Endothelial Cells: KDR-Mediated Induction of Egr3 and the Related Nuclear Receptors Nur77, Nurr1, and Nor1

  2003influential reference
• Dose finding with retroviral vectors: correlation of retroviral vector copy numbers in single cells with gene transfer efficiency in a cell population.

  2003cited by this paper
• Vascular endothelial growth factor secretion is an independent prognostic factor for relapse-free survival in pediatric acute myeloid leukemia patients.

  2002cited by this paper
• Overexpression of vascular endothelial growth factor (VEGF) and its cellular receptor KDR (VEGFR-2) in the bone marrow of patients with acute myeloid leukemia

  2002cited by this paper
• The core-binding factor β subunit is required for bone formation and hematopoietic maturation

  2002cited by this paper
• Requirement of Runx1/AML1/PEBP2αB for the generation of haematopoietic cells from endothelial cells

  2001cited by this paper
• Role of AP-1 and HIF-1 Transcription Factors in TGF-β Activation of VEGF Expression

  2001cited by this paper
• Interleukin-3 Stimulates Migration and Proliferation of Vascular Smooth Muscle Cells: A Potential Role in Atherogenesis

  2001cited by this paper
• Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes.

  2001cited by this paper
• Tissue specific regulation of VEGF expression during bone development requires Cbfa1/Runx2.

  2001cited by this paper
• Inhibition of both paracrine and autocrine VEGF/ VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias

  2001cited by this paper
• Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration.

  2000cited by this paper
• Cellular vascular endothelial growth factor is a predictor of outcome in patients with acute myeloid leukemia.

  1999cited by this paper
• Hepatocyte growth factor increases expression of vascular endothelial growth factor and plasminogen activator inhibitor-1 in human keratinocytes and the vascular endothelial growth factor receptor flk-1 in human endothelial cells.

  1999cited by this paper
• Cytokine-inducible growth factor gene expression in human umbilical endothelial cells.

  1999cited by this paper
• Expression of a knocked-in AML1-ETO leukemia gene inhibits the establishment of normal definitive hematopoiesis and directly generates dysplastic hematopoietic progenitors.

  1998cited by this paper
• The AML1/ETO(MTG8) and AML1/Evi-1 leukemia-associated chimeric oncoproteins accumulate PEBP2beta(CBFbeta) in the nucleus more efficiently than wild-type AML1.

  1998cited by this paper
• The AML1/ETO(MTG8) and AML1/Evi-1 Leukemia-Associated Chimeric Oncoproteins Accumulate PEBP2β(CBFβ) in the Nucleus More Efficiently Than Wild-Type AML1

  1998cited by this paper
• Negative regulation of granulocytic differentiation in the myeloid precursor cell line 32Dcl3 by ear-2, a mammalian homolog of Drosophila seven-up, and a chimeric leukemogenic gene, AML1/ETO.

  1998cited by this paper
• Induction of Vascular Endothelial Growth Factor by Tumor Necrosis Factor α in Human Glioma Cells(ヒトグリオーマ細胞における腫瘍壊死因子αによる血管内皮増殖因子の誘導)

  1997cited by this paper
• Embryonic lethality and impairment of haematopoiesis in mice heterozygous for an AML1-ETO fusion gene

  1997cited by this paper
• Induction of Vascular Endothelial Growth Factor by Tumor Necrosis Factor α in Human Glioma Cells

  1996cited by this paper
• AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis.

  1996cited by this paper
• Induction of vascular endothelial growth factor by tumor necrosis factor alpha in human glioma cells. Possible roles of SP-1.

  1996cited by this paper
• Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis.

  1995cited by this paper
• Hypoxic induction of human vascular endothelial growth factor expression through c-Src activation

  1995cited by this paper
• Indirect angiogenic cytokines upregulate VEGF and bFGF gene expression in vascular smooth muscle cells, whereas hypoxia upregulates VEGF expression only.

  1994cited by this paper
• Identification of breakpoints in t(8;21) acute myelogenous leukemia and isolation of a fusion transcript, AML1/ETO, with similarity to Drosophila segmentation gene, runt.

  1992cited by this paper
• The human Evi-1 gene is located on chromosome 3q24-q28 but is not rearranged in three cases of acute nonlymphocytic leukemias containing t(3;5)(q25;q34) translocations.

  1990cited by this paper
• Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line.

  1990cited by this paper
• Phase III comparison of the treatment of advanced gastrointestinal cancer with bolus weekly 5‐FU vs. methyl‐CCNU plus bolus weekly 5‐FU. A southwest oncology group study

  1976cited by this paper

• Post-translational modifications in diabetic retinopathy: a comprehensive review of mechanisms, crosstalk and clinical prospects.

  2025cites this paper
• Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth

  2024cites this paper
• Inhibition of Acute Myeloid Leukaemia Development by Bittersweet Based on miR-let-7a Regulating Vascular Endothelial Growth Factor A Resistance Mechanism

  2024cites this paper
• Leukemic stem cells hijack lineage inappropriate signalling pathways to promote their growth

  2023cites this paper
• Multiple Roles of the RUNX Gene Family in Hepatocellular Carcinoma and Their Potential Clinical Implications

  2023cites this paper
• Exosomes from chondrocytes overexpressing miR-214-3p facilitate M2 macrophage polarization and angiogenesis to relieve Legg Calvé-Perthes disease.

  2023cites this paper
• RUNX Family in Hypoxic Microenvironment and Angiogenesis in Cancers

  2022cites this paper
• Cancer Cells Promote Phenotypic Alterations in Hepatocytes at the Edge of Cancer Cell Nests to Facilitate Vessel Co-Option Establishment in Colorectal Cancer Liver Metastases

  2022cites this paper
• Identification of 1,3-thiazinan-4-one urea-Based Derivatives as Potent FLT3/VEGFR2 Dual Inhibitors for the Treatment of Acute Myeloid Leukemia

  2021cites this paper
• Comprehensive Analysis of Key Genes, Signaling Pathways and miRNAs in Human Knee Osteoarthritis: Based on Bioinformatics

  2021cites this paper
• Runt related transcription factor-1 plays a central role in vessel co-option of colorectal cancer liver metastases

  2021cites this paper
• Runt related transcription factor-1 plays a central role in vessel co-option of colorectal cancer liver metastases

  2021cites this paper
• RUNX1: an emerging therapeutic target for cardiovascular disease

  2020cites this paper
• Angiogenesis in acute myeloid leukemia

  2020cites this paper
• 1,25(OH)2D3 regulates the proangiogenic activity of pericyte through VDR‐mediated modulation of VEGF production and signaling of VEGF and PDGF receptors

  2019cites this paper
• RUNX1 inhibits proliferation and induces apoptosis of t(8;21) leukemia cells via KLF4-mediated transactivation of P57

  2019cites this paper
• Runx3 inhibits endothelial progenitor cell differentiation and function via suppression of HIF-1α activity.

  2019cites this paper
• Elucidation of Novel Therapeutic Targets for Acute Myeloid Leukemias with RUNX1-RUNX1T1 Fusion

  2019cites this paper
• Upregulation of RUNX1 Suppresses Proliferation and Migration through Repressing VEGFA Expression in Hepatocellular Carcinoma

  2019cites this paper
• Pharmacological inhibition of aberrant transcription factor complexes in inversion 16 acute myeloid leukemia.

  2018influential citation
• miR-125b promotes MLL-AF9-driven murine acute myeloid leukemia involving a VEGFA-mediated non-cell-intrinsic mechanism.

  2017cites this paper
• MYELOID NEOPLASIA miR-125 b promotes MLL-AF 9 – driven murine acute myeloid leukemia involving a VEGFA-mediated non – cell-intrinsic mechanism

  2017cites this paper
• Characterization of CADD522, a small molecule that inhibits RUNX2-DNA binding and exhibits antitumor activity

  2017cites this paper
• Roles of RUNX in Hypoxia-Induced Responses and Angiogenesis.

  2017cites this paper
• RUNX1 Regulates Migration, Invasion, and Angiogenesis via p38 MAPK Pathway in Human Glioblastoma

  2017cites this paper
• Endothelial progenitor cells in hematologic malignancies.

  2016cites this paper
• Biomimetic nanoparticles for siRNA delivery in the treatment of leukaemia.

  2014cites this paper
• c-myc but not Hif-1α-dependent downregulation of VEGF influences the proliferation and differentiation of HL-60 cells induced by ATRA.

  2013cites this paper
• Structure-activity relationship studies of pyrazolo[3,4-d]pyrimidine derivatives leading to the discovery of a novel multikinase inhibitor that potently inhibits FLT3 and VEGFR2 and evaluation of its activity against acute myeloid leukemia in vitro and in vivo.

  2013cites this paper
• Vascular endothelial growth factor signaling in acute myeloid leukemia

  2012cites this paper
• Runx1 is a tumor suppressor gene in the mouse gastrointestinal tract

  2012cites this paper
• Vascular Endothelial Growth Factor Levels in Childhood Acute Lymphoblastic and Myeloblastic Leukemia

  2012cites this paper