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)

Aplastic anaemia and paroxysmal nocturnal haemoglobinuria (PNH) are closely related disorders. In PNH, haematopoietic stem cells that harbour PIGA mutations give rise to blood elements that are unable to synthesize glycosylphosphatidylinositol (GPI) anchors. Because the GPI anchor is the receptor for the channel-forming protein aerolysin, PNH cells do not bind the toxin and are unaffected by concentrations that lyse normal cells. Exploiting these biological differences, we have developed two novel aerolysin-based assays to detect small populations of PNH cells. CD59 populations as small as 0.004% of total red cells could be detected when cells were pretreated with aerolysin to enrich the PNH population. All PNH patients displayed CD59-deficient erythrocytes, but no myelodysplastic syndrome (MDS) patient or control had detectable PNH cells before or after enrichment in aerolysin. Only one aplastic anaemia patient had detectable PNH red cells before exposure to aerolysin. However, 14 (61%) had detectable PNH cells after enrichment in aerolysin. The inactive fluorescent proaerolysin variant (FLAER) that binds the GPI anchors of a number of proteins on normal cells was used to detect a global GPI anchor deficit on granulocytes. Flow cytometry with FLAER showed that 12 out of 18 (67%) aplastic anaemia patients had FLAER-negative granulocytes, but none of the MDS patients or normal control subjects had GPI anchor-deficient cells. These studies demonstrate that aerolysin-based assays can reveal previously undetectable multilineage PNH cells in patients with untreated aplastic anaemia. Thus, clonality appears to be an early feature of aplastic anaemia.
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PMID:Multilineage glycosylphosphatidylinositol anchor-deficient haematopoiesis in untreated aplastic anaemia. 1170 52

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder characterized by a decrease or absence of glycosylphosphatidylinositol (GPI)-anchored molecules such as CD55 and CD59 from the surface of affected cells, resulting in intravascular hemolysis, cytopenia, and venous thrombosis. A PNH-like phenotype has been detected in various hematological disorders, mainly in aplastic anemia and myelodysplastic syndromes, but also in lymphoproliferative syndromes (LPSs). To the best of our knowledge, CD55- or CD59-deficient red cells have not been detected in plasma cell dyscrasias (PCDs). The aim of this study was the detection of CD55- and/or CD59-deficient red cell populations in patients with PCD. Seventy-seven patients were evaluated; 62 with multiple myeloma (MM), 7 with Waldenstrom macroglobulinemia (WM), 6 with monoclonal gammopathy of undetermined significance (MGUS), and 2 with heavy chain disease (HCD). The sephacryl gel microtyping system was applied; Ham and sucrose lysis tests were also performed on all samples with CD55- or CD59-negative populations. Red cells deficient in both molecules were detected in 10 (12.9%) of 77 patients with PCD: 2 (28.6%) of 7 with WM, 1 (16.6%) of 6 with MGUS, 6 (9.6%) of 62 with MM, and 1 of 2 patients with HCD. Isolated CD55 deficiency was found in 28.5% of all PCD patients, whereas isolated CD59 deficiency was not observed in any patients. These findings illustrate the existence of the PNH phenotype in the red cells of patients with PCD; further investigation is needed into the mechanisms and significance of this phenotype.
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PMID:Detection of CD55- and/or CD59-deficient red cell populations in patients with plasma cell dyscrasias. 1184 89

A minor population of blood cells deficient of glycosylphosphatidylinositol (GPI)-anchored membrane proteins is often detected in patients with aplastic anemia (AA), though the clinical significance of such paroxysmal nocturnal hemoglobinuria (PNH)-type cells remains unclear. To clarify this issue, we studied 164 patients with myelodysplastic syndrome (MDS) for the presence of CD55(-)CD59(-) granulocytes and red blood cells using sensitive flow cytometry. Among the different subgroups of MDS, a significant increase (ie, at least 0.003%) of PNH-type cells was detected in 21 of 119 patients with refractory anemia (RA); this frequency (17.6%) of RA patients with increased PNH-type cells (PNH(+) patients) was much lower than what we previously reported (52.0%) for AA patients. PNH(+) RA patients had distinct clinical features compared with RA patients without increased PNH-type cells (PNH(-) patients), such as less pronounced morphologic abnormality of blood cells, more severe thrombocytopenia, lower rates of karyotypic abnormality (4.8% vs 32.8%) and of progression to acute leukemia (0% vs 6.2%), higher probability of response to cyclosporine therapy (77.8% vs 0%), and higher incidence of HLA-DR15 (90.5% vs 18.5%). These data indicate that the presence of a minor population of PNH-type cells suggests a benign type of bone marrow failure, probably caused by an immunologic mechanism. To choose an appropriate therapy, peripheral blood should be tested using sensitive flow cytometry for the presence of PNH-type cells in all patients with bone marrow failure before treatment.
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PMID:Clinical significance of a minor population of paroxysmal nocturnal hemoglobinuria-type cells in bone marrow failure syndrome. 1239 38

Twelve transfusion-dependent patients with myelodysplastic syndrome (MDS) were treated with immunosuppressive therapy; 8 with cyclosporin A (CyA), 3 with CyA and antithymocyte globulin (ATG), one with ATG. G-CSF was combined in 10 patients. Eight patients who consisted of 4 treated with CyA, 3 with ATG/CyA, and one with ATG, achieved transfusion-independence. Responses were observed in 8/9 patients with refractory anemia, 0/3 patients with refractory anemia with excess of blast, although the recovery was incomplete in most cases. All of the CyA-responsive patients took drug-dependent courses. The presence of GPI-anchored protein-deficient granulocytes (CD11b+CD55-CD59-) was examined by flow cytometry after treatment in 6 responsive patients, and was demonstrated in 2 of them. HLA-DR15 was found in 5 of 7 responsive patients, suggesting that the presence of this allele may be associated with a good response to immunosuppressive therapy. All responsive patients had refractory anemia classified to IPSS Int-1, and had common conditions as follows: absence of chromosomal abnormality, short interval from diagnosis to therapy, and employment of ATG therapy.
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PMID:[Outcome of immunosuppressive therapy for myelodysplastic syndromes: results of 12 cases from a single institution]. 1246 26

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal stem cell disorder resulting from a somatic mutation in the hematopoietic stem cell. It is characterized by intravascular hemolysis, cytopenias, frequent infections, bone marrow hypoplasia, and a high incidence of life-threatening venous thrombosis. An absent glycosylphosphatidylinositol (GPI)-anchored receptor prevents several proteins from binding to the erythrocyte membrane. These include the complement-regulatory proteins, CD55 and CD59, whose absence results in enhanced complement-mediated lysis. Patients present with anemia and hemoglobinuria. Laboratory diagnosis includes the sucrose hemolysis test, Ham acid hemolysis test, and fluorescent-activated cell analysis. There is considerable overlap between PNH, aplastic anemia, and myelodysplastic syndrome and some cases evolve into acute leukemia. Treatment is mainly supportive consisting of transfusion therapy, anticoagulation, and antibiotic therapy. Hematopoietic stem cell transplantation may be curative.
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PMID:Paroxysmal nocturnal hemoglobinuria. 1531 92

To clarify some characteristics of phosphatidylinositol glycan-class A gene (PIG-A) mutations in aplastic anemia (AA) and myelodysplastic syndrome (MDS) patients compared with those in paroxysmal nocturnal hemoglobinuria (PNH) patients, we investigated PIG-A mutations in CD59- granulocytes and CD48- monocytes from seven AA, eight MDS, and 11 PNH Japanese patients. The most frequent base or type abnormalities of the PIG-A gene in AA and MDS patients were base substitutions or missense mutations, respectively, and deletions or frameshift mutations, respectively, in PNH patients. Several PIG-A mutations, most of which were statistically minor, were found in glycosylphosphatidylinositol-negative cells from all AA and MDS patients but not from all PNH patients. However, the common PIG-A mutations during the clinical course between CD59- granulocytes and/or CD48- monocytes from each AA or MDS patient, except for Case 5, were not found. PIG-A mutations were different between the granulocytes and monocytes from five AA and five MDS patients. Our results indicate that there were some characteristics of PIG-A mutations in AA and MDS patients compared with PNH patients and that several minor PNH clones in these patients occurred at random during the clinical course. This partly explains the transformation of AA or MDS to PNH at intervals.
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PMID:High frequency of several PIG-A mutations in patients with aplastic anemia and myelodysplastic syndrome. 1646 65

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematologic disorder that is manifested by complement-mediated hemolysis, venous thrombosis, and bone marrow failure and is one disorder of acquired bone marrow failure syndromes that include as aplastic anemia and myelodysplastic syndrome. Nowadays, acquired PNH should be understood as one of the disorders of PNH syndromes. These syndromes include congenital PNH (such as inherited complete CD59 deficiency and PNH with PIG-M mutations), because complement-mediated hemolysis and thrombosis are observed in association with defects of various factors associated with the complement regulatory pathway, including biosynthesis of the glycosylphosphatidylinositol (GPI) anchor. At present, how a "true" PNH clone in acquired PNH expands in the bone marrow remains unclear. Although several candidate genes, including the Wilms tumor gene, the early growth response gene, anti-apoptotic genes, and the high mobility group AT-hook 2 gene, that target corresponding proteins (excluding GPI-related proteins) have been reported, the evidence is insufficient to completely explain the diversity of the clinical and basic pathophysiology in acquired PNH. However, the hypothesis of expansion of a PNH clone due to the WT1 gene may explain various features of PNH.
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PMID:Heterogeneity in the molecular pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH) syndromes and expansion mechanism of a PNH clone. 1692 29

Although increased blood cell deficiency of glycosyl phosphatidylinositol-anchored membrane proteins has often been detected in patients with aplastic anemia (AA) and myelodysplastic syndrome (MDS), the clinical significance of such paroxysmal nocturnal hemoglobinuria (PNH)-type cells remains to be elucidated. We established a sensitive flow cytometric assay capable of detecting less than 0.01% of CD59-CD55- blood cells in a sample and used the assay to examine a large number of patients with bone marrow failure. An increase in the proportion of PNH-type cells was detectable in approximately 60% of all AA patients and in 20% of all refractory anemia (RA)-MDS patients. The increase was undetectable in patients with RA with an excessive number of blasts, acute myelogenous leukemia, multiple myeloma, or systemic lupus erythematosus. Our study showed that the presence of an increased number of PNH-type cells was predictive of a good response to immunosuppressive therapy and a favorable prognosis among patients with recently diagnosed AA and RA. A sensitive flow cytometric analysis for detection of a small population of PNH-type cells in peripheral blood cells is one of the most important examinations in the management of bone marrow failure.
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PMID:Clinical significance of a small population of paroxysmal nocturnal hemoglobinuria-type cells in the management of bone marrow failure. 1692 32

Coagulation abnormalities are frequently reported in hemolytic anemias (HA). Several pathophysiologic mechanisms are common to different HA. In this review three different hemolytic disorders will be discussed. In sickle cell disease and in beta-thalassemia, a thrombophilic status has been well documented as multifactorial involving hemostatic changes and activation of the coagulation cascade. Moreover, in such disorders, elevated levels of endothelial adhesion protein (ICAM-1, ELAM-1, VCAM-1, von Willebrand factor, and thrombomodulin) are often increased, suggesting that endothelial activation may be involved in vascular occlusion. As an additional mechanism of hypercoagulability in thalassemia, a procoagulant status of thalassemic red cells was recognized. The main clinical manifestation of paroxysmal nocturnal hemoglobinuria (PNH) is HA, and the most common complications are thrombosis, pancytopenia, and myelodysplastic syndrome or acute leukemia. The intravascular hemolysis is explained by a deficiency of glycosil phosphatidylinositol (GPI)-anchored complement regulatory proteins such as CD59 and CD55 on the membrane of red blood cells (RBCs), but the mechanism responsible for the increased incidence of thrombotic events in PNH remains unclear. Recent advances have been made in understanding the coagulation involvement in a heterogeneous group of diseases, thrombotic microangiopathies (TMA) characterized by microangiopathic hemolytic anemia and thrombocytopenia due to platelet clumping in the microcirculation, leading to ischemic organ dysfunction with neurologic symptoms and renal impairment.
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PMID:Coagulation in the pathophysiology of hemolytic anemias. 1802 12

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by absence of CD55 and CD59 from the surface of affected cells. PNH has been associated with myelodysplastic syndromes (MDS). The aim of our study was to estimate the prevalence of the PNH clone in MDS patients by detecting CD55 and CD59 deficiency. We studied 90 MDS patients: 19 patients with RA, 15 with refractory anemia with ringed sideroblasts (RARS), 18 with refractory anemia with excess of blasts (RAEB), 17 with refractory anemia with excess of blasts in transformation (RAEB-t), and 21 with chronic myelomonocytic leukemia (CMML). Twenty healthy individuals were also studied as the control group. We studied the PNH clone on granulocytes of these patients with the aid of flow cytometry. CD55- and CD59-deficient granulocytic populations were detected in 15.5% of MDS patients compared to 2.8% of normal individuals. Among the subgroups of the study, significant difference was present in three cases: (1) between CMML and control, (2) between CMML and RA, and (3) between CMML and RARS. These data indicate a possible association between PNH phenotype and MDS. MDS patients of worse prognosis (CMML) express more strongly the PNH clone compared to those of better prognosis (RA and RARS). Perhaps, the examination of MDS patients for the PNH clone by flow cytometry could provide us with a valuable prognostic tool.
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PMID:Detection of CD55- and CD59-deficient granulocytic populations in patients with myelodysplastic syndrome. 1815 79


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