The role of VEGF and a functional link between VEGF and p27Kip1 in acute myeloid leukemia.
Alterations in the expression and signalling pathways of vascular endothelial growth factor (VEGF) have been linked to the clinical features and pathogenesis of hematologic malignancies. In this study, we showed that VEGF protein expression was statistically significantly higher in the leukemic blasts than in the normal hematopoietic counterparts. A statistically significant correlation between expression of VEGF and p27(Kip1) was observed in bone marrows from 42 patients with acute myeloid leukemia (P<0.001). We further demonstrated that forced VEGF overexpression or autocrine VEGF stimulation of VEGFR-2 triggers proliferation and migration/invasion of U-937 leukemic cells, thereby inducing a more invasive tumor phenotype. U-937 cells overexpressing VEGF were resistant to all-trans-retinoic acid-(ATRA) or camptothecin-induced apoptosis. Finally, we showed that increased p27(Kip1) expression enhanced the ability of VEGF and VEGFR-2 to promote the migration of U-937 cells. Taken together, our results suggest that elevated level of VEGF may contribute to the adverse patient outcome by promoting cell growth, survival and migration of leukemic cells and by reducing the sensitivity of leukemic cells to therapeutic agents-induced apoptosis.
Wegiel
B
B
Department of Laboratory Medicine, Center for Molecular Pathology, Clinical Research Center, Lund University, University Hospital, Malmö, Sweden.
Ekberg
J
J
Talasila
K M
KM
Jalili
S
S
Persson
J L
JL
D001853:Bone Marrow / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology*
C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D050760:Cyclin-Dependent Kinase Inhibitor p27; D040301:Vascular Endothelial Growth Factor Receptor-2