Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes
Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes
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DOI：
10.1182/blood.v97.5.1427
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发表时间：
2001-03-01
期刊：
影响因子：
20.3
通讯作者：
List, AF
中科院分区：
文献类型：
--
作者：
Bellamy, WT;Richter, L;List, AF
血管内皮生长因子（VEGF）是一种强效的血管生成肽，其生物学效应包括调节造血干细胞发育、细胞外基质重塑以及炎症细胞因子的产生。为了阐明VEGF在骨髓增生异常综合征（MDS）患者中的潜在作用，对MDS骨髓（BM）中VEGF蛋白及其受体的表达以及其功能意义进行了评估。在正常供者的骨髓凝块切片中，在孤立的髓系成分中很少检测到低强度的细胞质VEGF表达。然而，慢性粒单核细胞白血病（CMML）中的单核细胞样前体细胞以强烈的细胞质模式表达VEGF，同时伴有Fit - 1或KDR受体或两者的膜性共表达。原位杂交证实了肿瘤性单核细胞中存在VEGF mRNA。在急性髓系白血病（AML）和其他MDS亚型中，在原始粒细胞和未成熟髓系成分中检测到VEGF与一种或两种受体的强烈共表达，而红系前体细胞和淋巴细胞缺乏VEGF及受体表达。异常定位的未成熟髓系前体细胞（ALIP）灶共表达VEGF和Fit - 1受体，提示自分泌细胞因子相互作用。VEGF的抗体中和作用抑制了15例CMML和RAEB - t患者标本中的9例的白血病集落形成单位（CFU）形成，而VEGF刺激了12例患者的白血病集落形成。VEGF活性的中和抑制了MDS骨髓单个核细胞和骨髓基质产生肿瘤坏死因子 - α和白细胞介素 - 1β，并促进了甲基纤维素培养中CFU - GEMM和红系爆式集落形成单位的形成。这些发现表明，VEGF的自分泌产生可能有助于CMML和MDS中白血病祖细胞的自我更新以及炎症细胞因子的释放，从而为ALIP及其在高危MDS中的不良预后相关性提供了生物学依据。（《血液》，2001年；97卷：1427 - 1434页）（©2001，美国血液学会）
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 Fit-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 Fit-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-alpha and interleukin-1 beta from MDS BM-mononuclear cells and BM-stroma 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. (Blood, 2001;97:1427-1434) (C) 2001 by The American Society of Hematology.