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Vascular endothelial growth factor (VEGF), a proangiogenic factor produced by most solid tumors has profound effects on lymphoid cell development, but the mechanism remains poorly understood. Since Notch signaling is necessary and sufficient for T- versus B-lineage commitment, we hypothesized that Notch signaling might mediate these effects. Using a mouse model with chronic administration of rhVEGF, we found that VEGF downregulated expression of Dll1 (Delta-like 1) and Dll4 (Delta-like 4) in the bone marrow and spleen microenvironments. Consistent with Dll1 and Dll4 signaling through Notch, expression of Notch target genes, Hes1 and Deltex1, was also decreased by VEGF in the bone marrow microenvironment. A specific VEGF-R2 antibody, DC101 reversed both the decreased expression of Notch ligands (Dll1 and Dll4) and Notch target genes (Hes1 and Deltex1) in vivo. These data show that VEGF inhibits Notch signaling in the bone marrow microenvironment by downregulating expression of Dll1 and Dll4 in vivo. Together with the observed pattern of aberrant lymphoid cell development (VEGF inhibits T cell development and marginal zone B cell generation and decreases T to B ratio), our data strongly suggest that Notch signaling mediates the effect of VEGF on lymphopoiesis. Our finding that VEGF inhibits expression of Notch ligands in hematopoiesis in vivo provides a mechanistic basis, and potential new molecular targets for the hematopoietic effects of pathologically elevated VEGF observed in many malignancies.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA