Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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-alpha and interleukin-1beta 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.
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PMID:Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes. 1151 Apr 70

We studied functional disturbances in hemopoietic microenvironment and cytokine production by stromal sublayer in long-term bone marrow cultures and peripheral blood macrophages from patients with various forms of myelodysplastic syndrome. Production of factors stimulating the growth of normal erythroid and granulocytic precursors by cells of the stromal sublayer from patients with refractory sideroblast anemia and refractory anemia with excess blasts is impaired compared to cells from healthy donors. The medium conditioned by macrophages from patients with chronic myelomonocytic leukemia displayed a higher ability to stimulate the growth of granulocytes and macrophages compared to media conditioned by cells from donors and patients with refractory sideroblast anemia and refractory anemia with excess blasts. Cultured stromal cells and macrophages produced tumor necrosis factor-alpha and interleukin-6. Their content in media conditioned by cells from patients with myelodysplastic syndrome surpassed that in healthy donors. Our results suggest that production of cytokines by stromal microenvironmental cells is impaired in patients with various forms of myelodysplastic syndrome.
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PMID:In vivo production of cytokines by bone marrow stromal cells and macrophages from patients with myelodysplastic syndrome. 1168 39

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor (TNF) family, binds to several cell-surface receptors with distinct functions (agonistic receptors 1 and 2 [TRAIL-R1, TRAIL-R2]; decoy receptors 3 and 4 [TRAIL-R3, TRAIL-R4]). Expression and function was characterized in patients with myelodysplastic syndromes (MDSs). While normal marrow showed negligible expression of TRAIL and receptors (except TRAIL-R3), TRAIL and all receptors were constitutively expressed in MDS marrow. Following TRAIL exposure, MDS marrow showed significant increases in apoptosis, whereas normal marrow, except for a subset of CD34+ precursors, did not (P =.012). Marrow from 21 patients with MDS was then propagated in long-term cultures in the presence or absence of TRAIL. While in advanced MDS (refractory anemia with excess blasts in transformation [RAEB-T] and tAML [MDS transformed into AML]), colony numbers decreased in the presence of TRAIL (63.0% +/- 10.4% of untreated group [100%]), numbers increased in patients with RA or RAEB (160.2% +/- 90.5% of untreated group). TRAIL eliminated preferentially clonally abnormal cells as identified by chromosomal markers. Thus, TRAIL and receptor expression differed significantly between normal and MDS marrow, and TRAIL modulated in vitro hemopoiesis in MDS dependent upon disease stage but not, to a detectable extent, in normal marrow.
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PMID:Expression of tumor necrosis factor-related apoptosis-inducing ligand, Apo2L, and its receptors in myelodysplastic syndrome: effects on in vitro hemopoiesis. 1169 91

Increased angiogenesis is important in the pathophysiology of solid tumors. Recent studies show that angiogenesis and angiogenic factors play an important role in hematological malignancies. Both acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are associated with a substantial increase in vascularity in the bone marrow as well as increased levels of various angiogenic factors including vascular endothelial growth factor (VEGF), basic fibroblast growth factor, angiogenin, angiopoietin-1, platelet-derived growth factor, hepatocyte growth factor, epidermal growth factor, tumor necrosis factor-alpha, and transforming growth factor-alpha and transforming growth factor-beta. Most of these angiogenic factors appear to be secreted by the neoplastic hematopoietic cells and appear to promote the growth and proliferation of the leukemic cells in an autocrine fashion. More importantly, angiogenic factors play a role in the clinical behavior and outcome of both AML and MDS. Despite significant overlap between MDS and AML in many aspects, higher levels of cellular VEGF and lower levels KDR are seen in MDS than in AML. Antiangiogenic therapy may play a role in AML and MDS and some differences in response may exist between MDS and AML.
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PMID:Angiogenesis in acute myeloid leukemia and myelodysplastic syndrome. 1181 14

Blockade of tumor necrosis factor (TNF)alpha by a soluble TNF receptor fusion protein (etanercept; Enbrel) improved in vitro hemopoiesis from the marrow of patients with myelodysplastic syndrome (MDS). Therefore, we enrolled 14 MDS patients (4 RA, 2 RARS, 6 RAEB, 2 CMML), 44-80 (median 60) years old, in a pilot trial. Etanercept, 25 mg, was given twice a week s.c. for 16 weeks (increased to three times a week if no response at 8 weeks). Among 12 evaluable patients, four had rises in hemoglobin by 1-1.5 gm/dl (three) or decreased transfusion requirements (one). Two patients had increased platelet counts (54% and 73%), and two increased neutrophils (63% and 120%). Baseline TNFalpha levels, determined in all patients, did not correlate with responses. Among eight marrows available for sequential in vitro assays, four showed increases in CFU-GM of 1.5- to 5-fold at 8 weeks, whereas three showed 3- to 10-fold decrements relative to baseline. Thus, etanercept treatment resulted in moderate improvements of cytopenias in some patients, while cell counts declined in others. Additional trials are needed to evaluate its clinical efficacy in MDS.
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PMID:Soluble TNF receptor fusion protein (etanercept) for the treatment of myelodysplastic syndrome: a pilot study. 1184 Feb 80

The therapeutic dilemma that confronts the management of patients with myelodysplastic syndromes (MDS) is illustrated by the absence of a Food and Drug Administration-approved agent with an indication for this disease. Clinical heterogeneity and inadequate understanding of the disease pathobiology have limited progress in the development of novel therapeutics. Preclinical investigations indicate that reciprocal interaction between the malignant clone and the microenvironment serve to create a hostile milieu that reinforces ineffective blood cell production. Ineffective hematopoiesis, the hallmark of MDS, arises from impaired progenitor responsiveness to normal trophic signals and excess local generation of inhibitory cytokines, which promote accelerated apoptotic loss of progenitors and their progeny. Evidence to support this model derives from cytokine neutralization studies and the direct relationship between plasma tumor necrosis factor-alpha concentration and DNA oxidation and glutathione depletion in malignant CD34+ progenitors. Recent investigations indicate that angiogenic molecules generated by malignant myelomonocytic precursors represent integral diffusable signals that reinforce leukemia progenitor self-renewal while promoting the generation of proapoptotic cytokines and medullary angiogenic response. The potential for leukemia evolution is compounded by epigenetic events including methylation silencing of the p15 proto-oncogene or activating ras point mutations. Delineation of such biologic features that are central to the pathobiology of MDS provides a reliable framework for the development of novel therapeutics. Antiangiogenic agents in clinical testing include vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors, thalidomide and related analogues, and the recombinant VEGF neutralizing antibody, bevacizumab. Agents whose actions may restore differentiation programs, such as the DNA methyltransferase inhibitors or histone deacetylase inhibitors, offer the prospect to promote effective hematopoiesis while impacting the potential for leukemia evolution. RAS farnesyl transferase inhibitors have shown encouraging preliminary results in acute myeloid leukemia and are currently under investigation in advanced MDS and chronic myelomonocytic leukemia. Arsenic trioxide (ATO) interacts with a spectrum of biologic targets that may be uniquely suited to MDS. ATO is a potent inducer of apoptosis in thiol-depleted malignant progenitors and neovascular endothelium, while promoting differentiation through histone acetylation and inactivation of transcriptional corepressors. The identification of relevant biologic targets in MDS has raised expectations for the development of disease-specific therapies for MDS in the years that follow.
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PMID:New approaches to the treatment of myelodysplasia. 1196 Dec 8

Labeling index (LI), apoptosis, levels of 2 pro-apoptotic cytokines tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta(TGF-beta), and the number of monocyte/macrophage cells that are the likely source of the cytokines were simultaneously measured in plastic-embedded bone marrow (BM) biopsy sections of 145 patients with myelodysplastic syndromes (MDS). TNF-alpha was correlated with TGF-beta (P = .001) and with monocyte/macrophage cells (P = .003). Patients with excess blasts in their marrows had a higher TGF-beta level (P = .01) and monocyte/macrophage number (P = .05). In a linear regression model,TGF-beta emerged as the most significant biological difference between patients who have excess of blasts and those who do not (P = .01). We conclude that in addition to TNF-alpha, TGF-beta also plays a significant role in the initiation and pathogenesis of MDS, and that a more precise definition of its role will likely identify better preventive and therapeutic strategies.
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PMID:Biological significance of proliferation, apoptosis, cytokines, and monocyte/macrophage cells in bone marrow biopsies of 145 patients with myelodysplastic syndrome. 1199 58

In vitro studies on the functional integrity of the hematopoietic microenvironment in myelodysplasia have been controversial. Although some of them suggest that such a microenvironment is functionally normal, there is increasing evidence indicating that there are alterations in the function of microenvironment (adherent) cell layers from myelodysplastic syndromes (MDS) marrow. Adherent cell layers developed in vitro, however, consist of a mixture of different cell types-mostly fibroblasts and macrophages-thus, it is not clear which cell type(s) is(are) functionally abnormal in this disorder. In order to address this issue, in the present study, we first assessed some functional properties of MDS-derived adherent cell layers, as a whole, and then we analyzed those same functional properties after separating these cells into two different populations: a fibroblast-enriched cell layer and a macrophage-enriched cell layer. When whole adherent layers from MDS patients were analyzed, no significant differences were observed, as compared to their normal counterparts, in terms of morphology and total cell number. A major difference, however, was observed when analyzing the production of the cytokines interleukin-6 (IL-6) and tumor necrosis factor (TNF-alpha). Indeed, adherent layers from MDS patients produced higher levels of these cytokines (2- and 22-fold, respectively), as compared to normal layers. When fibroblast- and macrophage-enriched cell layers were analyzed, a higher apoptotic index was observed in those derived from MDS marrow (4% of TUNEL-positive cells in normal fibroblast layers versus 27% in MDS-derived fibroblast layers; 7% of TUNEL-positive cells in normal macrophage layers versus 24% in MDS macrophage layers). Macrophages from MDS marrow produced significantly higher levels of TNF-alpha (nine-fold) than their normal counterparts. MDS-derived fibroblasts, on the other hand, produced higher levels of IL-6 (nine-fold), as compared to normal fibroblasts. Surprisingly, whereas normal fibroblasts showed a discrete production of TNF-alpha, we found a very high production of this cytokine in cultures of fibroblasts from MDS patients. In summary, in the present study we have demonstrated that, at least in vitro, both fibroblasts and macrophages from MDS bone marrow (BM) are functionally abnormal. Such abnormalities include an increased apoptotic index, as well as a high production of both IL-6 and TNF-alpha.
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PMID:In vitro characterization of hematopoietic microenvironment cells from patients with myelodysplastic syndrome. 1200 87

In low risk myelodysplastic syndrome (MDS), increased apoptosis of marrow cells is a reproducible finding. Cytokines may drive this apoptosis. Several studies have demonstrated elevated levels of tumor necrosis factor-alpha (TNF-alpha) in MDS. Soluble tumor necrosis factor receptor (TNFR:Fc) can eliminate biologically active TNF in vivo. This data provided the rationale for a clinical trial of TNFR:Fc in low risk MDS. Eligibility was limited to cytopenic MDS patients with < 10% marrow blasts. Secondary MDS was an exclusion. The study design was to administer 25mg TNFR:Fc twice a week for 10 weeks. Toxicity did not exceed grade 1. No responses were observed in the 10 treated patients and one had disease progression. At this dosing schedule, TNFR:Fc is unlikely to ameliorate cytopenias in low risk MDS.
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PMID:Pilot study of recombinant human soluble tumor necrosis factor receptor (TNFR:Fc) in patients with low risk myelodysplastic syndrome. 1219 63

We have detected trilineage myelodysplasia in two children recently diagnosed to have visceral leishmaniasis (V.L.), which led us to investigate retrospectively available peripheral blood and bone marrow aspirate smears of 5 children previously diagnosed as V.L. We saw that they also had trilineage myelodysplasia. We postulate that elevated levels of tumor necrosis factor-alpha (TNFalpha) may cause trilineage myelodysplasia in the patients with V.L. This nonclonal myelodysplasia may be responsible for pancytopenia along with hypersplenism, hemolysis and reticuloendothelial hyperplasia causing abnormal retention of iron in V.L.
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PMID:Myelodysplastic features in visceral leishmaniasis. 1241 May 74


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