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1 Molecular and Cell Biology Research, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada M4N 3M5;
2 Department of Medical Biophysics and 3 Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada M4N 3M5;
4 Department of Haematology, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London, United Kingdom; and
5 Novartis Pharma AG, Oncology Research, Basel, Switzerland
Requests for reprints: Robert S. Kerbel, Molecular and Cell Biology Research, Sunnybrook and Women's College Health Sciences Centre, S-218 Research Building, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5. Phone: (416) 480-5711; Fax: (416) 480-5703. E-mail: Robert.Kerbel{at}swchsc.on.ca
A large and diverse spectrum of oncogenes has been implicated as a contributor to angiogenesis in solid tumors based, in part, on its ability to induce proangiogenic growth factors such as vascular endothelial growth factor (VEGF), and the fact that various anti-oncogenic signaling inhibitor drugs have been shown to reverse such proangiogenic effects both in vitro and in vivo. Because leukemias are now also considered to be angiogenesis-dependent malignancies, we asked whether a similar paradigm might exist for the BCR-ABL oncogene and the Bcr-Abl targeting drug, STI-571 (imatinib mesylate), in the context of chronic myelogenous leukemia (CML) cells. We found that levels of VEGF expression in BCR-ABL-positive K562 cells were reduced in vitro by treatment with STI-571 in a dose-dependent fashion. Transfection of BCR-ABL into murine myeloid 32D and human megakaryocyte MO7e hematopoietic cells resulted in enhanced VEGF expression, which could be further elevated by the exposure to cytokines such as interleukin 3 and granulocyte macrophage colony-stimulating factor. We also found that conditioned media taken from 32D-p210-transfected cells could stimulate human umbilical vein endothelial cells by increasing phosphorylation of VEGF-R2/KDR and the downstream serine/threonine kinase PKB/Akt, an important regulator of endothelial cell survival. Moreover, amplification of BCR-ABL in STI-571-resistant cells was associated with elevated VEGF expression levels which could be reversed by treatment with higher concentrations of STI-571. Taken together, our results implicate BCR-ABL as a possible regulator of CML angiogenesis and raise the possibility that STI-571 could mediate some of its anti-CML properties in vivo through an angiogenesis-dependent mechanism.
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