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Blood, 15 May 2004, Vol. 103, No. 10, pp. 3883-3889. Prepublished online as a Blood First Edition Paper on January 15, 2004; DOI 10.1182/blood-2003-05-1634. This Article Full Text (PDF) All Versions of this Article: 2003-05-1634v1 103/10/3883    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Rosa Santos, S. C. Articles by Dias, S. Search for Related Content PubMed PubMed Citation Articles by Rosa Santos, S. C. Articles by Dias, S. Social Bookmarking                   What's this? Submitted May 22, 2003 Accepted December 31, 2003 Internal and external autocrine VEGF/KDR loops regulate the survival of subsets of acute leukemia through distinct signaling pathways Susana Constantino Rosa Santos and Sergio Dias* CIPM, Instituto Portugues de Oncologia Francisco Gentil, Lisboa, Portugal CIPM, Instituto Portugues de Oncologia Francisco Gentil, Lisboa, Portugal; Instituto Gulbenkian de Ciencia, Oeiras, Portugal * Corresponding author; email: sergidias{at}ipolisboa.min-saude.pt. Besides being expressed on endothelial cells, VEGF receptors (VEGFR) are also functional on subsets of leukemias, resulting in autocrine loops that sustain leukemia migration and proliferation. While recent evidence suggests VEGF supports hematopoietic stem cell survival via an internal loop, the molecular mechanisms whereby autocrine stimulation of VEGFR-2 (KDR) promotes leukemia growth are not well understood. Here we show on acute myeloid primary leukemias and cell lines, that VEGF/KDR autocrine loops operate both internally and externally. First, we demonstrate that KDR is constitutively phosphorylated and located to the nucleus of VEGF-producing leukemias. Treatment with anti-VEGF antibody, which acts externally, blocked KDR nuclear translocation, and inhibited NF-kB (p65 and c-rel) activation. In contrast, a KDR-specific intracellular inhibitor, failed to block KDR nuclear translocation, but inhibited the constitutive activation of MAPK/Erk and the PI 3-K/AKT pathways. Notably, treatment with the anti-VEGF antibody alone had little effect on cell survival, while the internal inhibitor induced leukemia apoptosis, and the 2 drugs produced synergistic effects, together and with chemotherapy, reducing cell survival to a larger extent than either agent alone. 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