Abstract
Increased angiogenesis in bone marrow (BM) is one of the characteristics of chronic myeloid leukemia (CML), a clonal myeloproliferative disorder that expresses a chimeric Bcr/Abl protein. Recently, the therapeutic strategy in CML has been totally modified with the development of a new drug: imatinib mesylate (STI571), a specific inhibitor of Bcr/Abl tyrosine kinase activity. The aim of our study was to determine, in patients with CML, the capacity of imatinib mesylate to modulate one of the most potent regulators of angiogenesis, the vascular endothelial growth factor (VEGF). In newly diagnosed CML, we observed significantly increased VEGF secretion by CML BM cells and significantly increased VEGF plasma concentrations. We showed that low plasma VEGF concentrations could be one of the characteristics of complete cytogenetic remission. To understand the molecular mechanisms leading to the inhibition of VEGF production by imatinib, we focused our experiments on the human cell line K562, which is Bcr/Abl positive. We demonstrated that imatinib inhibits VEGF gene transcription by targeting the Sp1 and Sp3 transcription factors. Taken together, our results highlight the potential prognostic value of VEGF concentrations in evaluating the evolution of CML patients treated with imatinib.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / administration & dosage*
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Antineoplastic Agents / pharmacology
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Benzamides
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Bone Marrow Cells / cytology
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Bone Marrow Cells / drug effects
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Bone Marrow Cells / metabolism
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DNA-Binding Proteins / metabolism
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Gene Expression / drug effects
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Humans
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Imatinib Mesylate
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K562 Cells
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / blood*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Phosphoinositide-3 Kinase Inhibitors
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Piperazines / administration & dosage*
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Piperazines / pharmacology
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Promoter Regions, Genetic
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Pyrimidines / administration & dosage*
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Pyrimidines / pharmacology
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RNA, Messenger / analysis
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Sp1 Transcription Factor / metabolism
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Sp3 Transcription Factor
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Transcription Factors / metabolism
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Transcriptional Activation / drug effects
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Vascular Endothelial Growth Factor A / blood*
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Antineoplastic Agents
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Benzamides
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DNA-Binding Proteins
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Phosphoinositide-3 Kinase Inhibitors
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Piperazines
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Pyrimidines
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RNA, Messenger
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SP3 protein, human
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Sp1 Transcription Factor
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Transcription Factors
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Vascular Endothelial Growth Factor A
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Sp3 Transcription Factor
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Imatinib Mesylate
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases