Immunophenotypic, cytogenetic and functional characterization of circulating endothelial cells in myelodysplastic syndromes

Abstract

Circulating endothelial cells (CECs) are associated with neoangiogenesis in various malignant disorders. Using flow cytometry, we studied CECs in 128 patients with myelodysplastic syndrome (MDS). MDS patients had higher CEC levels than controls (Po0.001), and an inverse relationship was found between CECs and international prognostic scoring system risk (r ¼ À0.55, Po0.001). There was a positive correlation between marrow microvessel density and CECs, low-risk patients showing the strongest association (r ¼ 0.62, Po0.001). We calculated a progenitor-to-mature CEC ratio, which was higher in MDS patients than in healthy subjects (Po0.001), the highest values were found at diagnosis. CECs assessed by flow cytometry positively correlated with the ability to produce endothelial colony-forming cells in vitro (ECFCs; r ¼ 0.57, P ¼ 0.021), which was significantly higher in MDS patients than in controls (P ¼ 0.011). Fluorescence in situ hybridization analysis showed that a variable proportion of CECs (from 40 to 84%) carried the same chromosomal aberration as the neoplastic clone, while endothelial cells isolated from in vitro assays were negative. This study suggests that CECs reflect the abnormal angiogenesis found in MDS, especially in the early stages of the disease. The increased number of functional endothelial progenitor cells in MDS strengthens the rationale for therapeutic interventions aimed at restoring a normal interaction between hematopoietic progenitors and marrow microenvironment.

Endothelial Progenitor Cell Dysfunction in Myelodysplastic Syndromes: Possible Contribution of a Defective Vascular Niche to Myelodysplasia

“…Among individuals with ECFCs, MDS patients had a significantly higher number of colonies than healthy controls (1.2 vs 0.2 ECFCs/10 7 cells, P < .0001, Figure 1). On the whole, the levels of ECFCs in our series of patients and the percentage of samples producing at least one ECFC are in good agreement with those reported by other authors using the same methodologies [16].…”

“…Although the increased level of ECFCs in these patients has been previously reported [16], our findings suggest that the molecular defects underlying MDS endothelial progenitor dysfunctions are likely primary in their nature, since these cells differ from their normal counterparts in both genetic and epigenetic profiles. Since the transplant of allogeneic endothelial progenitor cells in myelosuppressed mice shortens the duration of aplasia and fosters blood cell recovery, it is conceivable that circulating ECFCs normally contribute to the BM microvasculature homeostasis [35].…”

“…Although recent studies evidenced that in myeloproliferative neoplasms cells from the endothelial compartment harbor the disease-specific signature, i.e., the JAK2 V617F mutation [15,17], Della Porta et al demonstrated that ECFCs isolated from MDS patients do not show the chromosomal aberrations found in the neoplastic clone [16]. Because aberrant DNA methylation of CpG-rich promoters of a variety of genes is very frequent in MDS [17], we investigated in ECFCs an eventual deregulation of the epigenetic machinery.…”

The microenvironment in myelodysplastic syndromes: Niche-mediated disease initiation and progression

“…Thus, VEGF upregulation in MDS and numerous other hematologic malignancies is associated with increased vascularity, which may augment delivery of oxygen and nutrients for proliferating malignant clones. Another consequence of increased vascularity is increased endothelial cells observed in the marrow of a murine MDS model and in the circulation of patients with MDS [89, 106, 125]. VEGF stimulation of human umbilical vein endothelial cells has been reported to induce secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) [122, 126].…”

MDS prognostic scoring systems – Past, present, and future

“…A number of other features have been associated or correlated with prognosis in MDS, including BM microenvironment alterations (78-80), mean corpuscular volume (81), platelet mass (82), absolute lymphocyte count (83), basophilia and eosinophilia (84), hypoalbuminemia (85), and T-regulatory cells (86). A separate risk model for hypocellular MDS has also been proposed (87).…”