PMID- 12393646
OWN - NLM
STAT- MEDLINE
DCOM- 20030310
LR  - 20220331
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 100
IP  - 10
DP  - 2002 Nov 15
TI  - 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.
PG  - 3767-75
AB  - 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.
FAU - Mayerhofer, Matthias
AU  - Mayerhofer M
AD  - Department of Internal Medicine I, Division of Hematology and Hemostaseology, The 
      University of Vienna, Austria.
FAU - Valent, Peter
AU  - Valent P
FAU - Sperr, Wolfgang R
AU  - Sperr WR
FAU - Griffin, James D
AU  - Griffin JD
FAU - Sillaber, Christian
AU  - Sillaber C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20020718
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Endothelial Growth Factors)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Lymphokines)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Vascular Endothelial Growth Factors)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.10.2 (Fusion Proteins, bcr-abl)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Cell Line, Transformed
MH  - Endothelial Growth Factors/*biosynthesis/genetics
MH  - Fusion Proteins, bcr-abl/genetics/*physiology
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Intercellular Signaling Peptides and Proteins/*biosynthesis/genetics
MH  - Lymphokines/*biosynthesis/genetics
MH  - Mice
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Protein Kinase Inhibitors
MH  - Protein Kinases/*metabolism
MH  - *Protein Serine-Threonine Kinases
MH  - Proto-Oncogene Proteins/metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - RNA, Messenger/biosynthesis/drug effects
MH  - Signal Transduction
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Trans-Activators/*biosynthesis/genetics
MH  - Transcription Factors/*biosynthesis/genetics
MH  - Up-Regulation
MH  - Vascular Endothelial Growth Factor A
MH  - Vascular Endothelial Growth Factors
EDAT- 2002/10/24 04:00
MHDA- 2003/03/11 04:00
CRDT- 2002/10/24 04:00
PHST- 2002/10/24 04:00 [pubmed]
PHST- 2003/03/11 04:00 [medline]
PHST- 2002/10/24 04:00 [entrez]
AID - S0006-4971(20)54142-6 [pii]
AID - 10.1182/blood-2002-01-0109 [doi]
PST - ppublish
SO  - Blood. 2002 Nov 15;100(10):3767-75. doi: 10.1182/blood-2002-01-0109. Epub 2002 
      Jul 18.