Angiogenesis in acute promyelocytic leukemia: induction by vascular endothelial growth factor and inhibition by all-trans retinoic acid

Recent studies indicate that angiogenesis is important in the pathogenesis of leukemias, apart from its well-established role in solid tumors. In this study, the possible role of angiogenesis in acute promyelocytic leukemia ( APL) was explored. Bone marrow trephine biopsies from patients with APL sho wed significantly increased microvessel density and hot spot density compar ed with normal control bone marrow biopsies. To identify the mediators of a ngiogenesis in APL, quantitative and functional assays were performed using the NB4 APL cell line as a model system. Conditioned media (CM) from the N B4 cells strongly stimulated endothelial cell migration. CM from the NB4 ce lls contained high levels of vascular endothelial growth factor (VEGF) but not basic fibroblast growth factor (bFGF), Most important, the addition of neutralizing VEGF antibodies completely inhibited the ability of NB4 CM to stimulate endothelial cell migration, suggesting that APL angiogenesis is m ediated by VEGF. The effect of all-trans retinoic acid (ATRA) on APL angiog enesis was then studied. ATRA therapy resulted in a decrease in bone marrow microvessel density and hot spot density. CM from ATRA-treated APL cells d id not stimulate endothelial cell migration. Finally, quantitative assays s howed that ATRA treatment resulted in the abrogation of VEGF production by the NB4 cells. These results show that there is increased angiogenesis and VEGF production in APL and that ATRA therapy inhibits VEGF production and s uppresses angiogenesis, The addition of specific antiangiogenic agents to d ifferentiation therapy or chemotherapy should be explored.