{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T12:43:50Z","timestamp":1773837830621,"version":"3.50.1"},"reference-count":34,"publisher":"American Society of Hematology","issue":"4","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2006,2,15]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1182\/blood-2005-06-2530","type":"journal-article","created":{"date-parts":[[2005,10,26]],"date-time":"2005-10-26T09:23:34Z","timestamp":1130318614000},"page":"1608-1616","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":82,"title":["VEGFR-1 (FLT-1) activation modulates acute lymphoblastic leukemia localization and survival within the bone marrow, determining the onset of extramedullary disease"],"prefix":"10.1182","volume":"107","author":[{"given":"Rita","family":"Fragoso","sequence":"first","affiliation":[{"name":"From the Angiogenesis Laboratory, Centro Investigac\u0327a\u0303o Patobiologia Molecular, Instituto Portugue\u0302s de Oncologia Francisco Gentil (IPOFG), Lisboa, Portugal; the Servic\u0327o de Anatomia Patolo\u0301gica, IPOFG, Lisboa, Portugal; the Instituto de Medicina Molecular (IMM), Faculdade de Medicina, Lisboa, Portugal; the Instituto Gulbenkian de Cie\u0302ncia, Oeiras, Portugal; and ImClone Systems, New York, NY."}]},{"given":"Teresa","family":"Pereira","sequence":"additional","affiliation":[{"name":"From the Angiogenesis Laboratory, Centro Investigac\u0327a\u0303o Patobiologia Molecular, Instituto Portugue\u0302s de Oncologia Francisco Gentil (IPOFG), Lisboa, Portugal; the Servic\u0327o de Anatomia Patolo\u0301gica, IPOFG, Lisboa, Portugal; the Instituto de Medicina Molecular (IMM), Faculdade de Medicina, Lisboa, Portugal; the Instituto Gulbenkian de Cie\u0302ncia, Oeiras, Portugal; and ImClone Systems, New York, NY."}]},{"given":"Yan","family":"Wu","sequence":"additional","affiliation":[{"name":"From the Angiogenesis Laboratory, Centro Investigac\u0327a\u0303o Patobiologia Molecular, Instituto Portugue\u0302s de Oncologia Francisco Gentil (IPOFG), Lisboa, Portugal; the Servic\u0327o de Anatomia Patolo\u0301gica, IPOFG, Lisboa, Portugal; the Instituto de Medicina Molecular (IMM), Faculdade de Medicina, Lisboa, Portugal; the Instituto Gulbenkian de Cie\u0302ncia, Oeiras, Portugal; and ImClone Systems, New York, NY."}]},{"given":"Zhenping","family":"Zhu","sequence":"additional","affiliation":[{"name":"From the Angiogenesis Laboratory, Centro Investigac\u0327a\u0303o Patobiologia Molecular, Instituto Portugue\u0302s de Oncologia Francisco Gentil (IPOFG), Lisboa, Portugal; the Servic\u0327o de Anatomia Patolo\u0301gica, IPOFG, Lisboa, Portugal; the Instituto de Medicina Molecular (IMM), Faculdade de Medicina, Lisboa, Portugal; the Instituto Gulbenkian de Cie\u0302ncia, Oeiras, Portugal; and ImClone Systems, New York, NY."}]},{"given":"Jose\u0301","family":"Cabec\u0327adas","sequence":"additional","affiliation":[{"name":"From the Angiogenesis Laboratory, Centro Investigac\u0327a\u0303o Patobiologia Molecular, Instituto Portugue\u0302s de Oncologia Francisco Gentil (IPOFG), Lisboa, Portugal; the Servic\u0327o de Anatomia Patolo\u0301gica, IPOFG, Lisboa, Portugal; the Instituto de Medicina Molecular (IMM), Faculdade de Medicina, Lisboa, Portugal; the Instituto Gulbenkian de Cie\u0302ncia, Oeiras, Portugal; and ImClone Systems, New York, NY."}]},{"given":"Se\u0301rgio","family":"Dias","sequence":"additional","affiliation":[{"name":"From the Angiogenesis Laboratory, Centro Investigac\u0327a\u0303o Patobiologia Molecular, Instituto Portugue\u0302s de Oncologia Francisco Gentil (IPOFG), Lisboa, Portugal; the Servic\u0327o de Anatomia Patolo\u0301gica, IPOFG, Lisboa, Portugal; the Instituto de Medicina Molecular (IMM), Faculdade de Medicina, Lisboa, Portugal; the Instituto Gulbenkian de Cie\u0302ncia, Oeiras, Portugal; and ImClone Systems, New York, NY."}]}],"member":"234","reference":[{"key":"2019111900313660200_REF1","doi-asserted-by":"crossref","unstructured":"Gaynon PS, Desai AA, Bostrom BC, et al. Early response to therapy and outcome in childhood acute lymphoblastic leukemia: a review. Cancer. 1997;80: 1717-1726.","DOI":"10.1002\/(SICI)1097-0142(19971101)80:9<1717::AID-CNCR4>3.0.CO;2-B"},{"key":"2019111900313660200_","doi-asserted-by":"crossref","unstructured":"Rautonen J, Hovi L, Siimes MA. Slow disappearance of peripheral blast cells: an independent risk factor indicating poor prognosis in children with acute lymphoblastic leukemia. Blood. 1988;71: 989-991.","DOI":"10.1182\/blood.V71.4.989.989"},{"key":"2019111900313660200_","doi-asserted-by":"crossref","unstructured":"Rautonen J, Siimes MA. Can late relapse be predicted at initial diagnosis in childhood acute lymphoblastic leukemia? Eur J Haematol. 1989;43: 215-219.","DOI":"10.1111\/j.1600-0609.1989.tb00285.x"},{"key":"2019111900313660200_","doi-asserted-by":"crossref","unstructured":"Griffin TC, Shuster JJ, Buchanan GR, Murphy SB, Camitta BM, Amylon MD. Slow disappearance of peripheral blood blasts is an adverse prognostic factor in childhood T cell acute lymphoblastic leukemia: a Pediatric Oncology Group study. Leukemia. 2000;14: 792-795.","DOI":"10.1038\/sj.leu.2401768"},{"key":"2019111900313660200_REF5","doi-asserted-by":"crossref","unstructured":"Dusenbery KE, Howells WB, Arthur DC, et al. Extramedullary leukemia in children with newly diagnosed acute myeloid leukemia: a report from the Children's Cancer Group. J Pediatr Hematol Oncol. 2003;25: 760-768.","DOI":"10.1097\/00043426-200310000-00004"},{"key":"2019111900313660200_REF6","doi-asserted-by":"crossref","unstructured":"Rivera GK, Zhou Y, Hancock ML, et al. Bone marrow recurrence after initial intensive treatment for childhood acute lymphoblastic leukemia. Cancer. 2005;103: 368-376.","DOI":"10.1002\/cncr.20743"},{"key":"2019111900313660200_REF7","doi-asserted-by":"crossref","unstructured":"Gajjar A, Harrison PL, Sandlund JT, et al. Traumatic lumbar puncture at diagnosis adversely affects outcome in childhood acute lymphoblastic leukemia. Blood. 2000;96: 3381-3384.","DOI":"10.1182\/blood.V96.10.3381"},{"key":"2019111900313660200_REF8","doi-asserted-by":"crossref","unstructured":"Sandlund JT, Harrison PL, Rivera GK, et al. Persistence of lymphoblasts in bone marrow on day 15 and days 22 to 25 of remission induction predicts a dismal treatment outcome in children with acute lymphoblastic leukemia. Blood. 2002;100: 43-47.","DOI":"10.1182\/blood.V100.1.43"},{"key":"2019111900313660200_REF9","doi-asserted-by":"crossref","unstructured":"Gajjar A, Ribeiro R, Hancock ML, et al. Persistence of circulating blasts after 1 week of multiagent chemotherapy confers a poor prognosis in childhood acute lymphoblastic leukemia. Blood. 1995;86: 1292-1295.","DOI":"10.1182\/blood.V86.4.1292.bloodjournal8641292"},{"key":"2019111900313660200_REF10","doi-asserted-by":"crossref","unstructured":"Aguayo A, Giles F, Albitar M. Vascularity, angiogenesis and angiogenic factors in leukemias and myelodysplastic syndromes. Leuk Lymphoma. 2003;44: 213-222.","DOI":"10.1080\/1042819021000029777"},{"key":"2019111900313660200_REF11","doi-asserted-by":"crossref","unstructured":"Podar K, Anderson KC. The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications. Blood. 2005;105: 1383-1395.","DOI":"10.1182\/blood-2004-07-2909"},{"key":"2019111900313660200_REF12","doi-asserted-by":"crossref","unstructured":"Dias S, Shmelkov SV, Lam G, Rafii S. VEGF(165) promotes survival of leukemic cells by Hsp90-mediated induction of Bcl-2 expression and apoptosis inhibition. Blood. 2002;99: 2532-2540.","DOI":"10.1182\/blood.V99.7.2532"},{"key":"2019111900313660200_REF13","doi-asserted-by":"crossref","unstructured":"Dias S, Choy M, Alitalo K, Rafii S. Vascular endothelial growth factor (VEGF)-C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy. Blood. 2002;99: 2179-2184.","DOI":"10.1182\/blood.V99.6.2179"},{"key":"2019111900313660200_REF14","doi-asserted-by":"crossref","unstructured":"Giles FJ, Cooper MA, Silverman L, et al. Phase II study of SU5416\u2014a small-molecule, vascular endothelial growth factor tyrosine-kinase receptor inhibitor\u2014in patients with refractory myeloproliferative diseases. Cancer. 2003;97: 1920-1928.","DOI":"10.1002\/cncr.11315"},{"key":"2019111900313660200_REF15","doi-asserted-by":"crossref","unstructured":"Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23: 1011-1027.","DOI":"10.1200\/JCO.2005.06.081"},{"key":"2019111900313660200_REF16","doi-asserted-by":"crossref","unstructured":"Ferrara N. Vascular endothelial growth factor: basic science and clinical progres. Endocr Rev. 2004;25: 581-611.","DOI":"10.1210\/er.2003-0027"},{"key":"2019111900313660200_REF17","doi-asserted-by":"crossref","unstructured":"List AF, Glinsmann-Gibson B, Stadheim C, Meuillet EJ, Bellamy W, Powis G. Vascular endothelial growth factor receptor-1 and receptor-2 initiate a phosphatidylinositide 3-kinase-dependent clonogenic response in acute myeloid leukemia cells. Exp Hematol. 2004;32: 526-535.","DOI":"10.1016\/j.exphem.2004.03.005"},{"key":"2019111900313660200_REF18","doi-asserted-by":"crossref","unstructured":"Bellamy WT, Richter L, Sirjani D, et al. Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes. Blood. 2001;97: 1427-1434.","DOI":"10.1182\/blood.V97.5.1427"},{"key":"2019111900313660200_REF19","doi-asserted-by":"crossref","unstructured":"Vincent L, Jin DK, Karajannis MA, et al. Fetal stromal-dependent paracrine and intracrine vascular endothelial growth factor-a\/vascular endothelial growth factor receptor-1 signaling promotes proliferation and motility of human primary myeloma cells. Cancer Res. 2005;65: 3185-3192.","DOI":"10.1158\/0008-5472.CAN-04-3598"},{"key":"2019111900313660200_REF20","doi-asserted-by":"crossref","unstructured":"Aguayo A, Kantarjian H, Manshouri T, et al. Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. Blood. 2000;96: 2240-2245.","DOI":"10.1182\/blood.V96.6.2240"},{"key":"2019111900313660200_","doi-asserted-by":"crossref","unstructured":"Padro T, Ruiz S, Bieker R, et al. Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia. Blood. 2000;95: 2637-2644.","DOI":"10.1182\/blood.V95.8.2637"},{"key":"2019111900313660200_","doi-asserted-by":"crossref","unstructured":"Kini AR, Kay NE, Peterson LC. Increased bone marrow angiogenesis in B cell chronic lymphocytic leukemia. Leukemia. 2000;14: 1414-1418.","DOI":"10.1038\/sj.leu.2401825"},{"key":"2019111900313660200_","doi-asserted-by":"crossref","unstructured":"Kini AR, Peterson LA, Tallman MS, Lingen MW. Angiogenesis in acute promyelocytic leukemia: induction by vascular endothelial growth factor and inhibition by all-trans retinoic acid. Blood. 2001;97: 3919-3924.","DOI":"10.1182\/blood.V97.12.3919"},{"key":"2019111900313660200_REF24","doi-asserted-by":"crossref","unstructured":"Molica S, Vacca A, Levato D, Merchionne F, Ribatti D. Angiogenesis in acute and chronic lymphocytic leukemia. Leuk Res. 2004;28: 321-324.","DOI":"10.1016\/j.leukres.2003.08.001"},{"key":"2019111900313660200_REF25","doi-asserted-by":"crossref","unstructured":"Dias S, Hattori K, Zhu Z, et al. Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. J Clin Invest. 2000;106: 511-521.","DOI":"10.1172\/JCI8978"},{"key":"2019111900313660200_REF26","unstructured":"Hayashibara T, Yamada Y, Miyanishi T, et al. Vascular endothelial growth factor and cellular chemotaxis: a possible autocrine pathway in adult T-cell leukemia cell invasion. Clin Cancer Res. 2001;7: 2719-2726."},{"key":"2019111900313660200_REF27","doi-asserted-by":"crossref","unstructured":"Wang H, Keiser JA\u0301. Vascular endothelial growth factor upregulates the expression of matrix metalloproteinases in vascular smooth muscle cells: role of flt-1. Circ Res. 1998;83: 832-840.","DOI":"10.1161\/01.RES.83.8.832"},{"key":"2019111900313660200_REF28","doi-asserted-by":"crossref","unstructured":"Sawano A, Iwai S, Sakurai Y, et al. Flt-1, vascular endothelial growth factor receptor 1, is a novel cell surface marker for the lineage of monocyte-macrophages in humans. Blood. 2001;97: 785-791.","DOI":"10.1182\/blood.V97.3.785"},{"key":"2019111900313660200_REF29","unstructured":"Fetter AW, Rhinelander FW. Normal bone anatomy. In: Newton CD, Nunamaker DM, eds. Textbook of Small Animal Orthopaedics. Ithaca, NY: International Veterinary Information Service; 1985."},{"key":"2019111900313660200_REF30","doi-asserted-by":"crossref","unstructured":"Gerber HP, Vu TH, Ryan AM, Kowalski J, Werb Z, Ferrara N. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med. 1999;5: 623-628.","DOI":"10.1038\/9467"},{"key":"2019111900313660200_REF31","doi-asserted-by":"crossref","unstructured":"Street J, Bao M, deGuzman L, et al. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci U S A. 2002;99: 9656-9661.","DOI":"10.1073\/pnas.152324099"},{"key":"2019111900313660200_REF32","doi-asserted-by":"crossref","unstructured":"Mitra SK, Hanson DA, Schlaepfer DD. Focal adhesion kinase: in command and control of cell motility. Nat Rev Mol Cell Biol. 2005;6: 56-68.","DOI":"10.1038\/nrm1549"},{"key":"2019111900313660200_REF33","doi-asserted-by":"crossref","unstructured":"Wysoczynski M, Reca R, Ratajczak J, et al. Incorporation of CXCR4 into membrane lipid rafts primes homing-related responses of hematopoietic stem\/progenitor cells to an SDF-1 gradient. Blood. 2005;105: 40-48.","DOI":"10.1182\/blood-2004-04-1430"},{"key":"2019111900313660200_REF34","doi-asserted-by":"crossref","unstructured":"Gomez-Mouton C, Lacalle RA, Mira E, et al. Dynamic redistribution of raft domains as an organizing platform for signaling during cell chemotaxis. J Cell Biol. 2004;164: 759-768.","DOI":"10.1083\/jcb.200309101"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/107\/4\/1608\/469145\/zh800406001608.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/107\/4\/1608\/469145\/zh800406001608.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,4,10]],"date-time":"2020-04-10T13:53:47Z","timestamp":1586526827000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/107\/4\/1608\/133708\/VEGFR1-FLT1-activation-modulates-acute"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,2,15]]},"references-count":34,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2006,2,15]]}},"URL":"https:\/\/doi.org\/10.1182\/blood-2005-06-2530","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,2,15]]}}}