Vascular Endothelial Growth Factor Contributes to Adverse Patient Outcome in Acute Myeloid Leukemia by Promoting Cell Growth and Survival and by Reducing the Sensitivities of Leukemic Cells to Drug-Induced Apoptosis.

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that contributes to the regulation of hematopoietic stem cell development, extracellular matrix modelling and inflammatory cytokine generation. To study the potential role of VEGF in proliferation and apoptosis in acute myeloid leukemia, we evaluated the VEGF protein expression and its association with disease characteristics and patient outcome in 42 patients with acute myeloid leukemia (AML). In contrast to its weak expression in myeloid progenitors in normal bone marrows, high levels of VEGF expression was detected in 22 of the AML patients. Interestingly, VEGF expression significantly correlated with the expression of several major cell cycle regulatory proteins including cyclin A1, cyclin A2, cyclin E, CDK2 and p27. Log-rank test stratified by levels of VEGF expression revealed a clear trend with worse overall survival for patients with high levels of VEGF compared to those with low levels. Treatment of U-937 cells with recombinant VEGF protein resulted in an increased rate of proliferation. This suggested that VEGF may promote cell growth by mediating the cell cycle regulatory pathways. We further demonstrated that induced expression of VEGF promoted survival of leukemic cells and protected the cells from ATRA-induced apoptosis. Taken together, our studies demonstrated that increased expression of VEGF in AML patients was associated with worse patient outcome. Elevated levels of VEGF may contribute to the adverse outcome by promoting cell growth and survival of leukemic cells and reducing the sensitivity of leukemic cells to drug-induced apoptosis in AML patients.