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

The paradox of myelodysplastic syndromes (MDS) which present with pancytopenias despite cellular bone marrows (BM) was investigated by conducting detailed studies of proliferation and apoptosis in 89 MDS patients. Our results demonstrated a rapid rate of both proliferation as well as apoptosis. Levels of three cytokines, tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta) and interleukin-1 beta (IL-1 beta) were measured in the same patients. High levels of TNF-alpha were found to correlate with high levels of apoptosis in 83 MDS patients (P = 0.0045). We propose a dual role for TNF-alpha (or other cytokines) in the pathogenesis of MDS. On the one hand, TNF-alpha induces apoptosis in the maturing cells causing pancytopenia while on the other, it stimulates the proliferation of the primitive progenitors accounting for the hypercellular BM frequently seen in MDS. A new model for MDS is presented. The initial abnormality probably affects a primitive hemopoietic progenitor which acquires a growth advantage leading to monoclonal hemopoiesis, which in turn makes these cells susceptible towards acquiring additional mutations and appearance of cytogenetically marked (or unmarked) clones. Cytokines such as TNF-alpha whose source is presently unknown, then contribute towards the clinical syndrome of pancytopenia and hypercellularity.
 ...
PMID:Novel insights into the biology of myelodysplastic syndromes: excessive apoptosis and the role of cytokines. 876 10

The term myelodysplasia (MDS) refers to a group of bone marrow failure syndromes which are relatively rare in childhood. The pathogenesis of MDS is unknown, but a variety of chromosomal, molecular, and cytochemical abnormalities have been reported. We describe a 4-month-old female with MDS who presented with severe neutropenia and refractory anemia with excess blasts (RAEB). Bone marrow progenitor cell assays showed decreased erythroid and myeloid colony formation as compared to normal marrow, and the patient's serum further diminished colony formation of both her own and control marrow. These observations suggested the presence of a soluble factor inhibitory to hematopoiesis. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of total RNA derived from the patient's bone marrow mononuclear cells revealed highly elevated tumor necrosis factor-alpha (TNF-alpha) mRNA levels. Using a similar RT-PCR profile, TNF-alpha mRNA levels were found to be elevated in two other children with myelodysplasia. We conclude that TNF-alpha is produced in large amounts by bone marrow mononuclear cells of children with MDS, and we hypothesize that TNF-alpha plays an important role in the pathophysiology of the ineffective hematopoiesis observed in MDS.
 ...
PMID:Tumor necrosis factor-alpha suppresses hematopoiesis in children with myelodysplasia. 895 Mar 41

Extensive apoptosis or programmed cell death (PCD) of both hematopoietic (erythroid, myeloid, megakaryocytic) and stromal cells in myelodysplastic syndromes (MDS) cancels the high birth-rate resulting in ineffective hematopoiesis and has been demonstrated as the probable basis for peripheral cytopenias in MDS by our group. It is proposed that factors present in the microenvironment are inducing apoptosis in all the cells whether stromal or parenchymal. To investigate this hypothesis further, bone marrow biopsies from 46 MDS patients and eight normal individuals were examined for the presence of three cytokines, tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta) and granulocyte macrophage-colony stimulating factor (GM-CSF) and one cellular component, macrophages, by the use of monoclonal antibodies immunohistochemically. Results showed the presence of TNF-alpha and TGF-beta in 41/46 and 40/46 cases of MDS respectively, while only 15 cases showed the presence of GM-CSF. Further a significant direct relationship was found between the degree of TNF-alpha and the incidence of PCD (p= 0.0015). Patients who showed high PCD also had an elevated TNF-alpha level. Thus, the expression of high amounts of TNF-alpha and TGF-beta and low amounts of the viability factor GM-CSF may be responsible for the high incidence of PCD leading to ineffective hematopoiesis in MDS. Future studies will be directed at attempting to reverse the lesion in MDS by using anti-TNF-alpha drugs such as pentoxifylline.
 ...
PMID:Measurement of apoptosis, proliferation and three cytokines in 46 patients with myelodysplastic syndromes. 900 44

Bone marrow (BM) hypoplasia is a major cause of death in paroxysmal nocturnal hemoglobinuria (PNH). However, little is known about the molecular events leading to the hypoplasia. Considering the close pathologic association between PNH and aplastic anemia (AA), it is suggested that a similar mechanism operates in the development of their BM failure. Recent reports have indicated apoptosis-mediated BM suppression in AA. It is thus conceivable that apoptosis also operates to cause BM hypoplasia in PNH. If this is the case, PNH clones need to survive apoptosis and show considerable expansion leading to clinical manifestations. We report here that granulocytes obtained from 11 patients with PNH were apparently less susceptible than those from 20 healthy individuals to both spontaneous apoptosis without any ligands and that induced by anti-FAS (CD95) antibody in vitro. The patients' BM CD34+ cells were also resistant to apoptosis induced by treatment with tumor necrosis factor-alpha, interferon-gamma, and subsequently with anti-FAS antibody. In lymphocytes, the pathologic resistance was not discriminated from inherent resistance to apoptosis. Granulocytes from 13 patients with AA and 12 patients with myelodysplastic syndrome (MDS) exhibited similar resistance to apoptosis. CD34+ cells from MDS-BM also showed similar tendency. Thus, the comparative resistance to apoptosis supports the pathogenic implication of apoptosis in marrow injury of PNH and related stem cell disorders.
 ...
PMID:Apoptosis resistance of blood cells from patients with paroxysmal nocturnal hemoglobinuria, aplastic anemia, and myelodysplastic syndrome. 932 38

In patients with paroxysmal nocturnal hemoglobinuria (PNH), we measured plasma concentrations of endogenous hematopoiesis-regulatory cytokines to characterize bone marrow (BM) hypoplasia which is a major cause of death. Contrary to 10 healthy individuals, all 14 patients with PNH showed increases of erythropoietin (Epo) and granulocyte-colony stimulating factor (G-CSF). There were no signs of infection, renal dysfunction or hypoxia. The lower the hemoglobin level and granulocyte count, the higher the plasma Epo and G-CSF levels. In contrast, marked differences were not found in the levels of interleukin-3 (IL-3), tumor necrosis factor-alpha (TNF-alpha), stem cell factor (SCF), granulocyte/macrophage-colony stimulating factor (GM-CSF), or interferon-gamma) (IF-gamma). The cytokine profiles of PNH patients were quite similar to those of patients with aplastic anemia (AA) and myelodysplastic syndrome (MDS). The cytokine profiles may support a pathological relationship between PNH and these stem cell disorders.
 ...
PMID:Markedly high plasma erythropoietin and granulocyte-colony stimulating factor levels in patients with paroxysmal nocturnal hemoglobinuria. 947 72

Gene expression involving apoptosis in the hematopoietic system is reviewed. In normal and hematological disorders, Fas-Fas ligand and tumor necrosis factor-alpha-receptor interaction play a major role in enhancing apoptosis. On the other hand, bcl-2 or certain novel proteins (including FADD, RIP, TRADD and sentrin) prevent apoptosis. Apoptosis is involved in myelodysplastic syndrome and pathogenesis of leukemia. Expression of Fas antigen plays a role in negative regulation of hematopoiesis in the bone marrow as does interferon-gamma.
 ...
PMID:Apoptosis-gene expression in hematopoietic system: normal and pathological conditions (Review). 985 9

We previously reported excessive apoptosis and high levels of tumor necrosis factor-alpha (TNF-alpha) in the bone marrows of patients with myelodysplastic syndromes (MDS), using histochemical techniques. The present studies provide further circumstantial evidence for the involvement of TNF-alpha in apoptotic death of the marrow cells in MDS. Using our newly developed in situ double-labeling technique that sequentially employs DNA polymerase (DNA Pol) followed by terminal deoxynucleotidyl transferase (TdT) to label cells undergoing apoptosis, we have characterized DNA fragmentation patterns during spontaneous apoptosis in MDS bone marrow and in HL60 cells treated with TNF-alpha or etoposide (VP16). Clear DNA laddering detected by gel electrophoresis in MDS samples confirmed the unique length of apoptotic DNA fragments (180-200 bp). Surprisingly, however, phenotypically heterogeneous population of MDS cells as well as the homogenous population of HL60 cells showed three distinct labeling patterns after double labeling--only DNA-Pol reaction, only TdT reaction, and a combined DNA Pol + TdT reaction, albeit in different cohorts of cells. Each labeling pattern was found at all morphological stages of apoptosis. MDS mononuclear cells, during spontaneous apoptosis in 4 hr cultures, showed highest increase in double-labeled cells (DNA Pol + TdT reaction). Interestingly, this was paralleled by TNF-alpha-induced apoptosis in HL60 cells. In contrast, VP16 treatment of HL60 cells led to increased apoptosis in cells showing only TdT reaction. The double-labeling technique was applied to normal bone marrow and peripheral blood mononuclear cells after treatment with known endonucleases that specifically cause 3' recessed (BamHI), 5' recessed (PstI), or blunt ended (DraI) double-stranded DNA breaks. It was found that the DNA-Pol reaction in MDS and HL60 cells corresponds to 3' recessed DNA fragments, the TdT reaction to 5' recessed and/or blunt ended fragments, and a combined "DNA Pol + TdT reaction" corresponds to a copresence of 3' recessed with 5' recessed and/or blunt ended fragments. Clearly, therefore, apoptotic DNA fragments, in spite of a unique length, may have differently staggered ends that could be cell (or tissue) specific and be selectively triggered by different inducers of apoptosis. The presence of TNF-alpha-inducible apoptotic DNA fragmentation pattern in MDS supports its involvement in these disorders and suggests that anti-TNF-alpha (or anticytokine) therapy may be of special benefit to MDS patients, where no definitive treatment is yet available.
 ...
PMID:Evidence for involvement of tumor necrosis factor-alpha in apoptotic death of bone marrow cells in myelodysplastic syndromes. 988 4

WHAT IS HYPOPLASTIC ANEMIA? Aplastic anemia is a hematological disease characterized by pancytopenia and bone marrow hypoplasia. Acquired cases of aplastic anemia are almost all idiopathic and arise from unknown causes. Other cases of aplastic anemia are secondary and are caused by radiation, chemicals or viruses. PATHOPHYSIOLOGY: Aplastic anemia is manifested as a marked reduction in the number of pluripotent hematopoietic stem cells, but why this occurs is still uncertain. Some of the proposed causes include abnormalities of the hematopoietic stem cells, abnormalities in the hematopoietic microenvironment, and immunologically mediated damage to the hematopoietic stem cells (Figure 1). ABNORMALTIES OF THE HEMATOPOIETIC STEM CELLS: Patients with aplastic anemia, and long-term survivors in particular, are at increased risk of developing paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS), or acute myelocytic leukemia. This suggests that, in at least some of these patients, the hematopoietic stem cells themselves are abnormal. It also suggests that in some of these patients the blood cells are clonal (that is, all the blood cells are derived from a single pluripotent stem cell). In short, what these findings imply is that aplastic anemia may be caused by the emergence of an abnormal clone. Clonal hematopoiesis, however, can also be considered nothing more than a consequence. In other words, it is possible that hematopoiesis in this kind of patient is performed by a lone pluripotent stem cell that somehow managed to survive eradication. No definitive interpretation of clonal hematopoiesis has been agreed upon, and it is still a topic for future research. ABNORMAL HEMATOPOIETIC MICROENVIRONMENT: The presence of stromal cells, which form the microenvironment of bone marrow, is very important in hematopoiesis. Hematopoietic stem cells proliferate and differentiate either by adhering to stromal cells or by being stimulated by the various hematopoietic factors that stromal cells produce. Therefore, it is quite possible that aplastic anemia is caused by abnormalities in the hematopoietic microenvironment. However, many separate studies have demonstrated that the hematopoietic microenvironment in the vast majority of aplastic anemia cases is normal. IMMUNE MECHANISMS: Immunosuppressive agents are often effective in treating aplastic anemia, and therefore it is believed that immunological mechanisms contribute to the disease in more than half the cases. The following mechanisms have been proposed as causes for the onset of immunologically mediated aplastic anemia: * Decreases in Hematopoietic Factors Produced by Monocytes and Lymphocytes. Some patients with aplastic anemia show decreased production of interleukin 1 (IL-1) by peripheral blood monocytes, and it is possible that a drop in the concentration of this factor is linked to the onset of the disease [1]. It is also possible, however, that decreased IL-1 production by monocytes is not a cause of the disease, but merely a consequence. Moreover, no cases have been reported that exhibit reduced production of hematopoietic factors produced by lymphocytes such as GM-CSF, IL-3, or IL-6. * Damage by Cytokines that Suppress Hematopoiesis. It has been reported that increased levels of interferon &ggr; (IFN-&ggr;), which is produced by lymphocytes, and tumor necrosis factor &agr; (TNF-&agr;), which is produced by monocytes and macrophages, are found in the bone marrow and peripheral blood of aplastic anemia patients [2, 3]. These two factors act as suppressors of hematopoiesis, and it is possible that they contribute to the disease. The increase of these inflammatory cytokines in the bone marrow strongly suggests the presence of either specific or non-specific destruction of the hematopoietic stem cells by immunoregulatory cells. * Suppression of Hematopoiesis by Cytotoxic T Cells (Killer T Cells). Cases have been reported in which cytotoxic T cell clones that damage the autologous hematopoietic precursor cells are present [4]. Therefore, we can easily conceive of a mechanism in which these cytotoxic T cells specifically destroy the hematopoietic stem cells and cause aplastic anemia. * Suppression of Hematopoiesis by Natural Killer (NK) Cells. NK activity of aplastic anemia patients is depressed, and, generally speaking, it is highly unlikely that NK cells contribute to this condition. However, it has been reported that clonal NK cells are thought to cause the disease in patients exhibiting pancytopenia and bone marrow hypoplasia. Therefore, when this disease is diagnosed, a peripheral blood granular lymphocyte count and NK cell surface marker analysis should always be performed. DIAGNOSIS: A necessary condition for the diagnosis of aplastic anemia is the presence of pancytopenia. Moreover, it is necessary to rule out all other causes of pancytopenia. It is especially important in differential diagnosis to look for PNH and MDS. In cases of aplastic anemia there are patients that exhibit PNH during the course of the disease, and this condition is called aplastic anemia-PNH syndrome. It has recently been shown that bone marrow and peripheral blood cells in some patients diagnosed with aplastic anemia are partially lacking GPI anchor proteins (CD16, CD55, and CD59) [5]. Whether such patients become to exhibit aplastic anemia-PNH syndrome in the future remains to be elucidated. In MDS the bone marrow generally exhibits normoplasia or hyperplasia, and only in rare cases does it exhibit hypoplasia. This condition is referred to as hypoplastic MDS. Hypoplastic MDS can be differentiated from aplastic anemia by the presence of abnormal cell morphology that is sometimes accompanied by chromosomal abnormalities. TREATMENT:Aplastic anemia is treated with androgens, high-dose methylprednisolone, cyclosporin A (CyA), antithymocyte globulin (ATG), antilymphocyte globulin (ALG), hematopoietic growth factors such as G-CSF, and bone marrow transplantation. Interestingly, patients who require continuous CyA administration to maintain stable hematopoiesis have a specific HLA class II haplotype (DRB1*1501-DQA1*0102-DQB1*0602) [6]. Recent reports from EBMT SAA Working Party showed the excellent therapeutic result (response rate 82%) when severe cases were treated with ALG, CyA and G-CSF in combination [7].
 ...
PMID:Special Education: Aplastic Anemia. 1038 86

The mechanism that leads to hemopoietic failure in patients with myelodysplastic syndrome (MDS) is not well understood. There is evidence, however, that regulatory molecules such as tumor necrosis factor (TNF)-alpha, Fas (CD95), and Fas-ligand, which negatively affect hemopoiesis by way of apoptosis are upregulated. Here we analyzed marrow samples from 80 patients with MDS in regard to TNF-alpha and Fas-ligand levels and a possible correlation with various disease parameters and risk factors. TNF-alpha levels were elevated in comparison to samples from normal marrow donors, however, no significant correlation with FAB subtype, cytogenetic risk group or score by the International Prognostic Scoring System (IPSS) was observed. However, there was an inverse correlation between the cytogenetic risk category (low, intermediate, high) and levels of soluble Fas-ligand. The major source of TNF-alpha were mononuclear (non-stromal) cells which appeared to produce TNF-alpha at maximum levels. Limiting dilution analysis of CD34+ precursor cells showed that individually assayed cells, removed from companion cells that presumably provided negative signals such as TNF-alpha or Fas-ligand, were able to generate progressively increasing numbers of colonies. Stromal layers derived from MDS marrow did not have an inhibitory effect. In fact, higher colony numbers were obtained from both normal and MDS marrow derived hemopoietic precursors propagated on irradiated stromal layers from MDS marrow than on stromal layers from normal marrow. These results show that substantial numbers of normal hemopoietic precursors persist in MDS marrow. However, differentiation into mature cells is inhibited by negative signals originating from accessory or abnormal hemopoietic precursors in the non-adherent marrow fraction.
 ...
PMID:Negative regulators of hemopoiesis and stroma function in patients with myelodysplastic syndrome. 1075 92

Amifostine increases in vitro burst-forming unit-erythroid and colony-forming unit-granulocyte/granulcoyte-macrophage cultured from bone-marrow cells from patients with myelodysplastic syndrome (MDS). Several small clinical studies give divergent informations about the potential of amifostine as single agent to improve hematopoiesis in MDS patients. In these studies, patients with refractory anemia (RA), RA with excess of blasts (RAEB), and RAEB in transformation (RAEB-T) were analyzed together, resulting in response rates varying from 8% to 30%. The present multi-center study evaluated whether treatment with amifostine is of clinical benefit in patients with RA who are transfusion dependent. The effect on transfusion frequency as well as on platelets and absolute neutrophil count (ANC) was examined in 14 patients with RA [median age 67 years (55-72 years), male:female 9:5]. Four treatment cycles were planned, each consisting of intravenous amifostine at 200 mg/m2/day three times per week followed by a 2-week interval. Since tumor necrosis factor (TNF) alpha is a main suppressive cytokine for hematopoiesis in RA patients, serum samples for analyzing endogenous levels of TNF alpha were collected prior to the study and after four treatment cycles. In three patients (21%), reduced transfusion requirement with prolongation of the transfusion interval from 4 weeks to 8 weeks (two patients) and 4 weeks to 6 weeks was seen. An increase in ANC from 400/microliter to 2600/microliter and 200/microliter to 3400/microliter was observed in two patients. Platelets increased from 129,000/microliter to 277,000/microliter in an additional patient. In one patient, disease progression from RA to RAEB was observed. Serum TNF alpha levels were increased in MDS patients compared with normal controls (18.8 pg/ml vs 9.1 pg/ml), and there was no change during the treatment with amifostine (17.5 pg/ml). In conclusion, treatment with amifostine as a single agent was of limited benefit in patients with RA. The serum TNF alpha levels were unchanged during treatment with amifostine in RA patients.
 ...
PMID:Effect of treatment with amifostine used as a single agent in patients with refractory anemia on clinical outcome and serum tumor necrosis factor alpha levels. 1087 Apr 80


<< Previous 1 2 3 4 5 6 7 8 9 Next >>