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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the past 10 years a large amount of data has been published with respect to myelodysplasia. However, this newly emerged data, to date, has not been integrated into an all encompassing cohesive concept. The more knowledge we have about this illness to more precise diagnostic classifications, prognostications and eventually curative treatment modalities are possible. The ineffective haemopoiesis that is a hallmark of the disease may be explained by the apoptosis, hence antiapoptotic therapy, it appears, in some cases results in improvement. It is known that the malfunction of the mitochondria is responsible for accumulating the iron in sideroblastic anemia. The same mitochondrial malfunction may also be a factor in the development and progression of the non-sideroblastic forms of myelodysplasia as well. Promising research is on the way in examining the interaction between stroma cells of the bone marrow and the stem cells. Several publications study the hypothesis that the stroma also plays a significant role in the development of myelodysplasia clone. This role may be a causative one or perhaps a more passive/permissive one. This paper attempts to provide an overview of the newly emerged data, published in the most recent years, concerning myelodysplasia.
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PMID:[The biology of myelodysplastic syndromes]. 1527 3

A recurring translocation (X;20)(q13;q13) was found in four women ranging in age from 57 to 77 years. They had myelodysplasia, myelodysplasia with thrombocytopenia and pancytopenia, transforming to myelofibrosis, and myelodysplasia with sideroblastic anemia, respectively. The t(X;20) was the sole abnormality in three cases; one case also had a der(1;7)(q10;p10). Added to three previously reported cases, our four cases bring the total to seven; thus, t(X;20)(q13;q13) is a nonrandom translocation associated with myeloid disorders. Previous FISH studies showed that the breakpoint on the X is proximal to XIST. In one of our cases, the breakpoint on the X was shown to be proximal to Xq12, by FISH using a probe for the androgen receptor gene locus.
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PMID:Translocation (X;20)(q13;q13.3): a nonrandom abnormality in four patients with myeloid disorders. 1567 51

We describe a patient with a suspected myelodysplastic syndrome that developed in association with a neurologic disorder resembling subacute combined degeneration but without vitamin B12 deficiency. Ultimately, the hematologic manifestations and the neurologic syndrome were linked to severe copper deficiency. Prompt and complete reversal of the hematologic abnormalities occurred with copper replacement. Serum copper determination should be included in the work-up of patients with anemia and leukopenia of unclear etiology who have associated myeloneuropathy. The hematologic picture can resemble sideroblastic anemia or myelodysplastic syndrome. Hyperzincemia can be an accompanying abnormality even without exogenous zinc ingestion. The reason for the copper deficiency may not be evident.
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PMID:"Myelodysplasia," myeloneuropathy, and copper deficiency. 1643 90

The myelodysplastic syndromes (MDS) constitute a group of clonal stem cell disorders characterized by cytopenia, ineffective hematopoiesis, bone marrow dysplasia, and a risk of progression to acute myeloid leukemia (AML). Disease mechanisms can be divided into two main groups; those underlying the increased apoptosis of bone marrow progenitors, and those associated with progressive blast proliferation, and transformation to acute myeloid leukemia. The recently published WHO classification includes one subtype with a specific cytogenetic lesion, the 5q- syndrome, but otherwise classification of MDS is based solely on clinical and morphological criteria. Subsequently, few therapeutic options have been directed towards specific biological or molecular mechanisms in MDS. Progenitor apoptosis in MDS may be initiated by extrinsic and intrinsic mechanisms. The extrinsic pathway includes T-cell mediated bone marrow failure, for which antithymocyte globulin treatment may be an effective, as well as negative effects caused by the marrow microenvironment. New therapeutic options targeting the microenvironment include thalidomide and its analogue, lenalidomide, which has proven extremely effective for patients with 5q- syndrome. The erythroid apoptosis of in particular sideroblastic anemia is mediated by mitochondrial release of cytochrome c, which may be inhibited by treatment with erythropoietin and granulocyte-colony-stimulating-factor. Important mechanisms for disease progression are DNA hypermethylation, histone deacetylation, and possibly RAS mutations. Two new DNA hypomethylating agents, azacytidine and decitabine, have shown efficacy in patients with high-risk MDS, and may prolong time to progression. In conclusion, recent advances in the pathogenetic understanding of MDS have led to significant therapeutic progress.
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PMID:Strategies for biology- and molecular-based treatment of myelodysplastic syndromes. 1617 3

Valproic acid (VPA) inhibits histone deacetylase activity and induces differentiation of acute myeloid leukemia (AML) blasts in vitro. We observed clinical responses to VPA in patients with myelodysplastic syndrome (MDS) and AML. Here, we report follow-up data on 75 patients. Of these, 66 were started on VPA monotherapy, with later addition of all-trans retinoic acid (ATRA) in patients who did not respond or relapsed. Nine patients were treated with VPA + ATRA from the start. Median treatment duration was 4 months for VPA and 2 months for ATRA. Hematological improvement, according to international working group criteria for MDS, was observed in 18 patients (24%). Median response duration was 4 months. ATRA exerted no additional effect in patients receiving the combination from the start or benefited primary VPA nonresponders. However, of ten VPA responders who relapsed, four achieved a second response after addition of ATRA. Response rates were strongly dependent on disease type according to WHO classification. We found a response rate of 52% in MDS patients with a normal blast count (refractory sideroblastic anemia, refractory cytopenia with multilineage dysplasia, and refractory sideroblastic cytopenia with multilineage dysplasia). The response rate was 6% in refractory anemia with excess blasts (I + II), 16% in AML, and 0% in chronic myelomonocytic leukemia. Bone marrow blast count was the only variable that predicted responses. We conclude that VPA is clinically useful in low-risk MDS. For patients with high-risk MDS, VPA may be combined with chemotherapy or demethylating drugs. If patients relapse after an initial response to VPA, ATRA has the potential to induce a prolonged second response.
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PMID:Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia. 1627 Feb 13

Erythroid dysplasia is the pathologic hallmark of myelodysplastic syndromes (MDS). To develop a quantitative flow-cytometry approach to its evaluation, we analyzed the expression of CD71, CD105, cytosolic H-ferritin (HF), cytosolic L-ferritin (LF) and mitochondrial ferritin (MtF) in erythroblasts from 104 MDS patients, 69 pathologic control patients and 19 healthy subjects. Six-parameter, 4-color flow cytometry was employed, and data were expressed as mean fluorescence intensity. Compared with pathologic and healthy controls, MDS patients had higher expression of HF (P < 0.001) and CD105 (P < 0.001), and lower expression of CD71 (P < 0.001). MtF was specifically detected in MDS with ringed sideroblasts, and there was a close relationship between its expression and Prussian blue staining (r = 0.89, P < 0.001). In vitro cultures of myelodysplastic hematopoietic progenitors showed that both HF and MtF were expressed at a very early stage of erythroid differentiation, and that MtF expression is specifically related to mitochondrial iron loading. A classification function based on expression levels of HF, CD71 and CD105 allowed us to correctly classify > 95% of MDS patients. This flow-cytometry approach provides an accurate quantitative evaluation of erythroid dysplasia and allows a reliable diagnosis of sideroblastic anemia, and may therefore be a useful tool in the work-up of patients with MDS.
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PMID:Flow cytometry evaluation of erythroid dysplasia in patients with myelodysplastic syndrome. 1649 94

Mitochondria are involved in hematopoietic cell homeostasis through multiple ways such as oxidative phosphorylation, various metabolic processes and the release of cytochrome c in the cytosol to trigger caspase activation and cell death. In erythroid cells, the mitochondrial steps in heme synthesis, iron (Fe) metabolism and Fe-sulfur (Fe-S) cluster biogenesis are of particular importance. Mutations in the specific delta-aminolevulinic acid synthase (ALAS) 2 isoform that catalyses the first and rate-limiting step in heme synthesis pathway in the mitochondrial matrix, lead to ineffective erythropoiesis that characterizes X-linked sideroblastic anemia (XLSA), the most common inherited sideroblastic anemia. Mutations in the adenosine triphosphate-binding cassette protein ABCB7, identified in XLSA with ataxia (XLSA-A), disrupt the maturation of cytosolic (Fe-S) clusters, leading to mitochondrial Fe accumulation. In addition, large deletions in mitochondrial DNA, whose integrity depends on a specific DNA polymerase, are the hallmark of Pearson's syndrome, a rare congenital disorder with sideroblastic anemia. In acquired myelodysplastic syndromes at early stage, exacerbation of physiological pathways involving caspases and the mitochondria in erythroid differentiation leads to abnormal activation of a mitochondria-mediated apoptotic cell death pathway. In contrast, oncogenesis-associated changes at the mitochondrial level can alter the apoptotic response of transformed hematopoietic cells to chemotherapeutic agents. Recent findings in mitochondria metabolism and functions open new perspectives in treating hematopoietic cell diseases, for example various compounds currently developed to trigger tumor cell death by directly targeting the mitochondria could prove efficient as either cytotoxic drugs or chemosensitizing agents in treating hematological malignancies.
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PMID:Mitochondria in hematopoiesis and hematological diseases. 1689 88

Three patients with pregnancy-induced pancytopenia also exhibited variable features of sideroblastic anemia and amegakaryocytic thrombocytopenia. Treatment with anti-thymocyte globulin proved highly effective in two cases and a spontaneous remission occurred in the third. This illness is distinct from the more commonly reported incidental association of pregnancy with classic aplastic anemia. Its differentiation from myelodysplasia is also emphasized.
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PMID:Pregnancy-induced pancytopenia with cellular bone marrow: distinctive hematologic features. 1703 Dec 46

Refractory Anemia with Ring Sideroblasts (RARS) is an acquired myelodysplastic syndrome (MDS) characterized by an excess iron accumulation in the mitochondria of erythroblasts. The pathogenesis of RARS and the cause of this unusual pattern of iron deposition remain unknown. We considered that the inherited X-linked sideroblastic anemia with ataxia (XLSA/A) might be informative for the acquired disorder, RARS. XLSA/A is caused by partial inactivating mutations of the ABCB7 ATP-binding cassette transporter gene, which functions to enable transport of iron from the mitochondria to the cytoplasm. Furthermore, ABCB7 gene silencing in HeLa cells causes an accumulation of iron in the mitochondria. We have studied the role of ABCB7 in RARS by DNA sequencing, methylation studies, and gene expression studies in primary CD34(+) cells and in cultured erythroblasts. The DNA sequence of the ABCB7 gene is normal in patients with RARS. We have investigated ABCB7 gene expression levels in the CD34(+) cells of 122 MDS cases, comprising 35 patients with refractory anemia (RA), 33 patients with RARS and 54 patients with RA with excess blasts (RAEB), and in the CD34(+) cells of 16 healthy controls. We found that the expression levels of ABCB7 are significantly lower in the RARS group. RARS is thus characterized by lower levels of ABCB7 gene expression in comparison to other MDS subtypes. Moreover, we find a strong relationship between increasing percentage of bone marrow ring sideroblasts and decreasing ABCB7 gene expression levels. Erythroblast cell cultures confirm the low levels of ABCB7 gene expression levels in RARS. These data provide an important link between inherited and acquired forms of sideroblastic anemia and indicate that ABCB7 is a strong candidate gene for RARS.
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PMID:The role of the iron transporter ABCB7 in refractory anemia with ring sideroblasts. 1839 82

Anemia is the most frequent peripheral cytopenia observed in myelodysplastic syndromes (MDS) and has been recognized among the most important factors affecting the outcome of patients with MDS. In patients who are not candidates for potentially curative approaches, therapeutic options for symptomatic anemia include red blood cell (RBC) transfusion and iron chelation, hematopoietic growth factors, immunosuppression, immune-modulatory drugs, and hypomethylating agents. In about 40% of patients, regular RBC transfusions are the only therapeutic option that can be offered. The onset of a regular transfusion requirement significantly worsens the survival of patients with MDS. Transfusion-dependent patients invariably develop secondary iron overload. Elevated serum ferritin was proven to be associated with worse survival in transfusion-dependent patients, and recent data obtained using magnetic resonance imaging show both hepatic and myocardial iron accumulation in heavily transfused patients. According to evidence-based guidelines, patients with sideroblastic anemia, 5q- syndrome, or other forms of refractory anemia, in whom long-term transfusion therapy is likely, are recognized as the best candidates to receive iron chelation therapy. In addition, patients who are candidates for allogeneic stem cell transplantation might also benefit from chelation therapy because iron overload is associated with increased transplantation-related mortality. RBC transfusions and iron chelation are the mainstay of therapy for many individuals with MDS. However, critical issues remain to be clarified in order to optimize treatment, including the identification of target hemoglobin levels to prevent anemia-related morbidity and more accurate information on the effect of iron-mediated organ damage on the outcome of patients with MDS.
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PMID:Red blood cell transfusion therapy and iron chelation in patients with myelodysplastic syndromes. 1977 58


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