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

Blood. 2002 Nov 15;100(10):3767-75. doi: 10.1182/blood-2002-01-0109. Epub 2002 Jul 18.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Transformed
  • Endothelial Growth Factors / biosynthesis*
  • Endothelial Growth Factors / genetics
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / physiology*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Intercellular Signaling Peptides and Proteins / biosynthesis*
  • Intercellular Signaling Peptides and Proteins / genetics
  • Lymphokines / biosynthesis*
  • Lymphokines / genetics
  • Mice
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein Kinase Inhibitors
  • Protein Kinases / metabolism*
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / drug effects
  • Signal Transduction
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases
  • Trans-Activators / biosynthesis*
  • Trans-Activators / genetics
  • Transcription Factors / biosynthesis*
  • Transcription Factors / genetics
  • Up-Regulation
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • Endothelial Growth Factors
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Intercellular Signaling Peptides and Proteins
  • Lymphokines
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Trans-Activators
  • Transcription Factors
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Protein Kinases
  • MTOR protein, human
  • mTOR protein, mouse
  • Fusion Proteins, bcr-abl
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Sirolimus