{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T10:14:09Z","timestamp":1791108849052,"version":"4.1.0"},"reference-count":49,"publisher":"American Society of Hematology","issue":"5","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2001,3,1]]},"abstract":"<jats:p>Vascular endothelial growth factor (VEGF) is a potent angiogenic peptide with biologic effects that include regulation of hematopoietic stem cell development, extracellular matrix remodeling, and inflammatory cytokine generation. To delineate the potential role of VEGF in patients with myelodysplastic syndrome (MDS), VEGF protein and receptor expression and its functional significance in MDS bone marrow (BM) were evaluated. In BM clot sections from normal donors, low-intensity cytoplasmic VEGF expression was detected infrequently in isolated myeloid elements. However, monocytoid precursors in chronic myelomonocytic leukemia (CMML) expressed VEGF in an intense cytoplasmic pattern with membranous co-expression of the Flt-1 or KDR receptors, or both. In situ hybridization confirmed the presence of VEGF mRNA in the neoplastic monocytes. In acute myelogenous leukemia (AML) and other MDS subtypes, intense co-expression of VEGF and one or both receptors was detected in myeloblasts and immature myeloid elements, whereas erythroid precursors and lymphoid cells lacked VEGF and receptor expression. Foci of abnormal localized immature myeloid precursors (ALIP) co-expressed VEGF and Flt-1 receptor, suggesting autocrine cytokine interaction. Antibody neutralization of VEGF inhibited colony-forming unit (CFU)-leukemia formation in 9 of 15 CMML and RAEB-t patient specimens, whereas VEGF stimulated leukemia colony formation in 12 patients. Neutralization of VEGF activity suppressed the generation of tumor necrosis factor-\u03b1 and interleukin-1\u03b2 from MDS BM\u2013mononuclear cells and BM\u2013stroma and promoted the formation of CFU-GEMM and burst-forming unit-erythroid in methylcellulose cultures. These findings indicate that autocrine production of VEGF may contribute to leukemia progenitor self-renewal and inflammatory cytokine elaboration in CMML and MDS and thus provide a biologic rationale for ALIP and its adverse prognostic relevance in high-risk MDS.<\/jats:p>","DOI":"10.1182\/blood.v97.5.1427","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T12:46:47Z","timestamp":1027774007000},"page":"1427-1434","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":280,"title":["Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes"],"prefix":"10.1182","volume":"97","author":[{"given":"William T.","family":"Bellamy","sequence":"first","affiliation":[{"name":"From the Department of Pathology, the Department of Hematology\/Oncology, and the Bone Marrow Transplant Program, The 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Tucson, AZ."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betty","family":"Glinsmann-Gibson","sequence":"additional","affiliation":[{"name":"From the Department of Pathology, the Department of Hematology\/Oncology, and the Bone Marrow Transplant Program, The Arizona Cancer Center, University of Arizona, Tucson, AZ."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvette","family":"Frutiger","sequence":"additional","affiliation":[{"name":"From the Department of Pathology, the Department of Hematology\/Oncology, and the Bone Marrow Transplant Program, The Arizona Cancer Center, University of Arizona, Tucson, AZ."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas M.","family":"Grogan","sequence":"additional","affiliation":[{"name":"From the Department of Pathology, the Department of Hematology\/Oncology, and the Bone Marrow Transplant Program, The Arizona Cancer Center, University of Arizona, Tucson, 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factors.","volume":"5","author":"Merchav","year":"1991","journal-title":"Leukemia."},{"key":"2020021221251038900_B3","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1182\/blood.V89.5.1690","article-title":"Erythropoietin-induced activation of STAT5 is impaired in the myelodysplastic syndrome.","volume":"89","author":"Hoefsloot","year":"1997","journal-title":"Blood."},{"key":"2020021221251038900_B4","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1182\/blood.V86.1.268.bloodjournal861268","article-title":"Apoptosis in bone marrow biopsy samples involving stromal and hematopoietic cells in 50 patients with myelodysplastic syndromes.","volume":"86","author":"Raza","year":"1995","journal-title":"Blood."},{"key":"2020021221251038900_B5","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/0925-5710(96)00455-0","article-title":"Novel insights into biology of myelodysplastic syndromes: excessive apoptosis and the role of cytokines.","volume":"63","author":"Raza","year":"1996","journal-title":"Int J Hematol."},{"key":"2020021221251038900_B6","doi-asserted-by":"crossref","first-page":"2049","DOI":"10.1038\/sj.leu.2400844","article-title":"Overexpression of tumor necrosis factor (TNF)-\u03b1 and interferon (INF)-\u03b1 by bone marrow cells from patients with myelodysplastic syndromes.","volume":"11","author":"Kitagawa","year":"1997","journal-title":"Leukemia."},{"key":"2020021221251038900_B7","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1046\/j.1365-2141.1998.00933.x","article-title":"A role for tumor necrosis factor-alpha, fas and fas-ligand in marrow failure associated with myelodysplastic syndrome.","volume":"103","author":"Gersuk","year":"1998","journal-title":"Br J Haematol."},{"key":"2020021221251038900_B8","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1046\/j.1365-2141.1997.4373247.x","article-title":"Oxidative DNA damage in CD34+ myelodysplastic cells is associated with intracellular redox changes and elevated plasma tumor necrosis factor-\u03b1 concentration.","volume":"99","author":"Peddie","year":"1997","journal-title":"Br J Haematol."},{"key":"2020021221251038900_B9","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1056\/NEJM199512283332608","article-title":"Clinical applications of research on angiogenesis.","volume":"333","author":"Folkman","year":"1995","journal-title":"N Engl J Med."},{"key":"2020021221251038900_B10","first-page":"206","article-title":"Tumor angiogenesis.","volume-title":"The Molecular Basis of Cancer.","author":"Folkman","year":"1995"},{"key":"2020021221251038900_B11","first-page":"728","article-title":"Expression of vascular endothelial growth factor (VEGF) and its receptors in hematopoietic malignancies.","volume":"59","author":"Bellamy","year":"1999","journal-title":"Cancer Res."},{"key":"2020021221251038900_B12","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1126\/science.2479986","article-title":"Vascular endothelial growth factor is a secreted angiogenic mitogen.","volume":"246","author":"Leung","year":"1989","journal-title":"Science."},{"key":"2020021221251038900_B13","first-page":"1029","article-title":"Vascular permeability factor\/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis.","volume":"146","author":"Dvorak","year":"1995","journal-title":"Am J Pathol."},{"key":"2020021221251038900_B14","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/0955-0674(95)80116-2","article-title":"Proteolytic remodeling of extracellular matrix.","volume":"7","author":"Birkedal-Hansen","year":"1995","journal-title":"Curr Opin Cell Biol."},{"key":"2020021221251038900_B15","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/376062a0","article-title":"Failure of blood island formation and 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