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Prepublished online as a Blood First Edition Paper on July 18, 2002; DOI 10.1182/blood-2002-01-0109. This Article Full Text (PDF) All Versions of this Article: 2002-01-0109v1 100/10/3767    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mayerhofer, M. Articles by Sillaber, C. Search for Related Content PubMed PubMed Citation Articles by Mayerhofer, M. Articles by Sillaber, C. Social Bookmarking                   What's this? Submitted January 16, 2002 Accepted July 5, 2002 BCR/ABL Induces Expression of Vascular Endothelial Growth Factor and its Transcriptional Activator, Hypoxia Inducible Factor-1, through a Pathway Involving PI3-Kinase and the Mammalian Target of Rapamycin (mTOR) Matthias Mayerhofer, Peter Valent, Wolfgang R Sperr, James D Griffin, and Christian Sillaber* Department of Hematology & Hemostaseology, The University of Vienna, Vienna, Vienna, Austria Department of Adult Oncology, Dana Farber Cancer Institute, Boston, MA, USA * Corresponding author; email: christian.sillaber{at}univie.ac.at. Recent data suggest that vascular endothelial growth factor (VEGF), a cytokine involved in autocrine growth of tumor cells and tumor-angiogenesis, is upregulated and plays a potential role in myelogenous leukemias. In chronic myelogenous leukemia (CML), VEGF is expressed at high levels in the bone marrow and peripheral blood. We here show that the CML-associated oncogene BCR/ABL induces VEGF gene expression in growth factor-dependent Ba/F3 cells. Whereas starved cells were found to contain only baseline levels of VEGF mRNA, Ba/F3 cells induced to express BCR/ABL exhibited substantial amounts of VEGF mRNA. BCR/ABL also induced VEGF promoter activity and increased VEGF protein levels in Ba/F3 cells. Moreover, BCR/ABL was found to promote expression of functionally active hypoxia inducible factor-1 (HIF-1), a major transcriptional regulator of VEGF gene expression. BCR/ABL-induced VEGF gene expression was counteracted by the phosphoinositide 3-kinase (PI3-kinase) inhibitor LY294002 and rapamycin, an antagonist of mTOR, but not by inhibition of the mitogen-activated protein kinase pathway. Similarly, BCR/ABL-dependent HIF-1 expression was inhibited by addition of LY294002 and rapamycin. Together, our data show that BCR/ABL induces VEGF- and HIF-1 gene expression through a pathway involving PI3-kinase and mTOR. 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