Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes

Vascular endothelial growth factor (VEGF) is a potent angiogenic peptide wi th biologic effects that include regulation of hematopoietic stem cell deve lopment, extracellular matrix remodeling, and inflammatory cytokine generat ion. To delineate the potential role of VEGF in patients with myelodysplast ic syndrome (MDS), VEGF protein and receptor expression and its functional significance in MDS bone marrow (BM) were evaluated. In BM clot sections fr om normal donors, low-intensity cytoplasmic VEGF expression was detected in frequently in isolated myeloid elements. However, monocytoid precursors in chronic myelomonocytic leukemia (CMML) expressed VEGF in an intense cytopla smic pattern with membranous co-expression of the Fit-1 or KDR receptors, o r both. In situ hybridization confirmed the presence of VEGF mRNA in the ne oplastic monocytes. In acute myelogenous leukemia (AML) and other MDS subty pes, intense co-expression of VEGF and one or both receptors was detected i n myeloblasts and immature myeloid elements, whereas erythroid precursors a nd lymphoid cells lacked VEGF and receptor expression. Foci of abnormal loc alized immature myeloid precursors (ALIP) co-expressed VEGF and Fit-1 recep tor, 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 form ation in 12 patients. Neutralization of VEGF activity suppressed the genera tion of tumor necrosis factor-alpha and interleukin-1 beta from MDS BM-mono nuclear cells and BM-stroma and promoted the formation of CFU-GEMM and burs t-forming unit-erythroid in methylcellulose cultures. These findings indica te 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 Soci ety of Hematology.