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Blood, 15 February 2006, Vol. 107, No. 4, pp. 1608-1616. Prepublished online as a Blood First Edition Paper on October 25, 2005; DOI 10.1182/blood-2005-06-2530. This Article Full Text (PDF) Erratum (v107,p3057) All Versions of this Article: 2005-06-2530v1 107/4/1608    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 Fragoso, R. Articles by Dias, S. Search for Related Content PubMed PubMed Citation Articles by Fragoso, R. Articles by Dias, S. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 29, 2005 Accepted October 7, 2005 VEGFR-1 (FLT-1) activation modulates acute lymphoblastic leukemia localization and survival within the bone marrow, determining the onset of extramedullary disease Rita Fragoso, Teresa Pereira, Yan Wu, Zhenping Zhu, Jose Cabecadas, and Sergio Dias* Angiogenesis Lab-Centro de Investigacao Patobiologia Molecular, Instituto Portugues de Oncologia Francisco Gentil, Lisbon, Portugal; Angiogenesis Lab, Instituto Gulbenkian de Ciencia, Oeiras, Portugal Servico de Anatomia Patologica, Instituto Portugues de Oncologia Francisco Gentil, Lisbon, Portugal ImClone Systems, New York, New York, USA Angiogenesis Lab-Centro de Investigacao Patobiologia Molecular, Instituto Portugues de Oncologia Francisco Gentil, Lisbon, Portugal; Centro Investigacao Patobiologia Molecular, Instituto de Medicina Molecular, Faculdade de Medicina, Lisbon, Portugal; Angiogenesis Lab, Instituto Gulbenkian de Ciencia, Oeiras, Portugal * Corresponding author; email: sergidias{at}ipolisboa.min-saude.pt. The presence of persistent circulating leukemia cells, or engrafted into extramedullary tissues, is a bad prognostic factor for acute leukemia patients. However, little is known about the mechanisms that regulate the exit of leukemia cells from the bone marrow (BM) microenvironment. We reveal that Vascular Endothelial Growth Factor Receptor 1 (FLT-1) modulates acute leukemia distribution within the BM, along VEGF and PlGF gradients, regulating leukemia survival and exit into the peripheral circulation. FLT-1 activation on acute lymphoblastic leukemia (ALL) cells results in cell migration and proliferation in vitro, while in vivo FLT-1 overexpressing cells accumulate in the BM epiphysis of NOD-SCID recipients, and are detected in circulation 2 weeks after inoculation. In turn, FLT-1 neutralization affects leukemia localization (now in the BM diaphysis), increases leukemia apoptosis and impedes the exit of ALL cells, prolonging the survival of inoculated mice. We demonstrate further that FLT-1-induced cell migration involves actin polimerization and lipid raft formation. Taken together, we show that FLT-1 regulates the BM localization of ALL cells, determining their survival and exit into the circulation, and ultimately the survival of inoculated recipients. FLT-1 targeting on subsets of acute leukemias may delay the onset of extramedullary disease, which may be advantageous in combinatorial therapeutic settings. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. C Caires, J. de Avila, and D. J McLean Vascular endothelial growth factor regulates germ cell survival during establishment of spermatogenesis in the bovine testis Reproduction, October 1, 2009; 138(4): 667 - 677. [Abstract] [Full Text] [PDF] N. Rahimi, T. E. Golde, and R. D. 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G. da Silva, and S. Dias Characterization and clinical relevance of circulating and biopsy-derived endothelial progenitor cells in lymphoma patients Haematologica, April 1, 2007; 92(4): 469 - 477. [Abstract] [Full Text] [PDF] Y. Wu, Z. Zhong, J. Huber, R. Bassi, B. Finnerty, E. Corcoran, H. Li, E. Navarro, P. Balderes, X. Jimenez, et al. Anti-vascular endothelial growth factor receptor-1 antagonist antibody as a therapeutic agent for cancer. Clin. Cancer Res., November 1, 2006; 12(21): 6573 - 6584. [Abstract] [Full Text] [PDF]

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