title: VEGFR-1 (FLT-1) activation modulates acute lymphoblastic leukemia localization and survival within the bone marrow, determining the onset of extramedullary disease.
abstract: 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.
authors.affiliation: Angiogenesis Laboratory, Centro Investigação Patobiologia Molecular, Instituto Português de Oncologia Francisco Gentil (IPOFG), Rua Professor Lima Basto, 1099-023 Lisboa, Portugal.
authors.forename: Rita
authors.initials: R
authors.lastname: Fragoso
authors.forename: Teresa
authors.initials: T
authors.lastname: Pereira
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Zhenping
authors.initials: Z
authors.lastname: Zhu
authors.forename: José
authors.initials: J
authors.lastname: Cabeçadas
authors.forename: Sérgio
authors.initials: S
authors.lastname: Dias
mesh_terms: D017209:Apoptosis; D001706:Biopsy; D001853:Bone Marrow / Q000473:pathology*; D018076:DNA, Complementary / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000401:mortality / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics*
chemical_list: D018076:DNA, Complementary; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1