BCR/ABL induces expression of vascular endothelial growth factor and its transcriptional activator, hypoxia inducible factor-1alpha, through a pathway involving phosphoinositide 3-kinase and the mammalian target of rapamycin.

Recent data suggest that vascular endothelial growth factor (VEGF), a cytokine involved in autocrine growth of tumor cells and tumor angiogenesis, is up-regulated 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 show here 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 the 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 mammalian target of rapamycin (mTOR), but not by inhibition of the mitogen-activated protein kinase pathway. Similarly, BCR/ABL-dependent HIF-1alpha expression was inhibited by the addition of LY294002 and rapamycin. Together, our data show that BCR/ABL induces VEGF- and HIF-1alpha gene expression through a pathway involving PI3-kinase and mTOR. BCR/ABL-induced VEGF expression may contribute to the pathogenesis and increased angiogenesis in CML.