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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.
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NEOPLASIA
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,
José Cabeçadas, and
Sérgio Dias
From the Angiogenesis Laboratory, Centro Investigação Patobiologia Molecular, Instituto Português de Oncologia Francisco Gentil (IPOFG), Lisboa, Portugal; the Serviço de Anatomia Patológica, IPOFG, Lisboa, Portugal; the Instituto de Medicina Molecular (IMM), Faculdade de Medicina, Lisboa, Portugal; the Instituto Gulbenkian de Ciência, Oeiras, Portugal; and ImClone Systems, New York, NY.
The presence of persistent circulating leukemia cells, or engrafted into extramedullary tissues, is a bad prognostic factor for patients with acute leukemia. 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, whereas in vivo FLT-1-overexpressing cells accumulate in the BM epiphysis of nonobese diabetic-severe combined immunodeficient (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 polymerization 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.
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