While it is established that an angiogenic switch marks escape from tumor dormancy in xenograft models, the molecular pathways involved in the control of tumor cell proliferation or survival by angiogenesis remain substantially uncharted. I'll present data supporting the hypothesis that signals stemming from angiogenic endothelial cells regulate the behaviour of dormant cancer cells. Recently, we demonstrated that the Notch ligand Dll4, induced by angiogenic factors in endothelial cells, triggers Notch3 activation in neighbouring tumor cells and promotes a tumorigenic phenotype. We further dissected molecular events downstream of Notch in T acute lymphoblastic leukemia (T-ALL) xenografts and observed that MKP-1 levels - a broadly expressed phosphatase - are controlled by Notch3 by regulation of protein ubiquitination and stability but not MKP-1 gene expression. Notch3 and MKP-1 levels are consistently up-regulated in aggressive compared to dormant tumors, and this is accompanied by opposite variations in the levels of active p38, a canonical MKP-1 target. A good correlation between Notch3 and MKP-1 levels was observed in T-ALL primary samples and T-ALL cell lines. Silencing Notch3 by RNA interference or g-secretase treatment, or stimulation of Notch3 by the Dll4 ligand substantially reduced MKP-1 levels in T-ALL cells in vitro. Concordant results have been obtained by neutralizing Dll4 both in a co-colture system in vitro and in vivo. Attenuation of MKP-1 levels by shRNA did not affect proliferation, whereas it significantly increased T-ALL cell death following drug treatment or serum starvation. Importantly, engraftment of MKP-1 deficient T-ALL cells in immunodeficient mice was markedly impaired compared to controls. Altogether, these results elucidate a novel angiogenesis-driven mechanism involving the Notch and MAPK pathways that controls survival of T-ALL cells and tumor dormancy.