Cases reported "Myelodysplastic Syndromes"

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1/4. Vitamin K2 induces apoptosis of a novel cell line established from a patient with myelodysplastic syndrome in blastic transformation.

    We have previously reported that vitamin K2 (VK2) has a potent apoptosis inducing activity toward various types of primary cultured leukemia cells including acute myelogenous leukemia arising from myelodysplastic syndromes (MDS). We established a novel cell line, designated MDS-KZ, from a patient with MDS in blastic transformation, and further investigated the effects of VK2 using this novel cell line. MDS-KZ shows complex chromosomal anomaly including -4, 5q-, -7, 13q , 20q-, consistent with that seen in the original patient. culture of MDS-KZ cells in RPMI1640 medium containing 10% FBS lead to steady but very slow proliferation with a doubling time of 14 days. However, the cellular growth rate was significantly accelerated in the presence of various growth factors such as granulocyte colony-stimulating factor, stem cell factor, granulocyte-macrophage colony-stimulating factor, interleukin-3, and thrombopoietin. Most of the cultured cells show the morphological features of myeloblasts. They are positive for CD7, CD33, CD34, CD45, CD117, and HLA-DR. However, about 10% of the cells are more mature metamyelocytes and neutrophils with various dysplastic characteristics such as pseudo-Pelger nuclear anomaly and hypersegmentation, suggesting a potential for differentiation in this cell line. As previously reported for cultured primary leukemia cells, exposure to VK2, but not to VK1, resulted in induction of apoptosis of MDS-KZ cells in a dose-dependent manner (IC50: 5 microM). In addition, VK2 treatment induced down-regulation of BCL-2 and up-regulation of BAX protein expression with concomitant activation of caspase-3 (CPP32). A tetrapeptide functioning as antagonist of caspase-3, Ac-DEVD-H, suppressed the VK2-induced inhibition of cell growth, suggesting that caspase-3 is, at least in part, involved in VK2-induced apoptosis. These observations suggest that the MDS-KZ cell line can serve as a model for the study of the molecular mechanisms of VK2-induced apoptosis.
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ranking = 1
keywords = apoptosis
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2/4. mastocytosis cells bearing a c-kit activating point mutation are characterized by hypersensitivity to stem cell factor and increased apoptosis.

    mastocytosis is characterized by abnormal infiltration of mast cells into various organs. An activating mutation in c-kit, involving an A --> T substitution at nucleotide 2648 has recently been described in some patients with mastocytosis. We describe a 12-year-old girl with this mutation in her bone marrow cells at diagnosis with a myelodysplastic syndrome (MDS) without evidence of mastocytosis, and then in peripheral blood mononuclear cells 1 year later after the emergence of mastocytosis. The role of the c-Kit receptor and its ligand stem cell factor (SCF) in the pathogenesis of the disease was analysed in marrow cell clonogenic assays. We show that the genetic abnormalities in the patient resulted in factor-independent growth and hypersensitivity of primitive progenitors to SCF, with increased production of mast cells. Increased apoptosis and cluster formation, consistent with the myelodysplastic nature of the disorder, accompanied accumulation of abnormal cells with increasing concentrations of SCF.
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ranking = 0.625
keywords = apoptosis
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3/4. Contributions of flow cytometry to the analysis of the myelodysplastic syndrome.

    As the population of north america ages, the incidence of MDS is likely to rise. Epidemiologic survey instruments need to be put in place to document changes in the incidence. The basic mechanism of disease in MDS is largely unknown. No unifying, testable hypothesis is yet available, but apoptosis, with mitochondria playing a key role, are central to any discussion of MDS. Cytogenetic abnormalities have not provided an explanation of MDS but are of diagnostic and prognostic significance. The emergence of immunologic factors is of major importance and emphasizes the need for early detection. flow cytometry can be used diagnostically to exclude other causes of cytopenias, document the phenotypic manifestations of myeloid dysmaturation, and provide blast enumeration. The distinctions between MDS and acute leukemia are arbitrary, and the process should be conceptualized as a continuum. There is a need for continued work to establish minimal diagnostic criteria for MDS. The current prognostic scoring systems do not incorporate findings from the newer technologies.
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ranking = 0.125
keywords = apoptosis
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4/4. The role of mitochondrial-mediated apoptosis in a myelodysplastic syndrome secondary to congenital deletion of the short arm of chromosome 4.

    OBJECTIVE: myelodysplastic syndromes (MDS) are characterized by peripheral cytopenia and ineffective hematopoiesis. In adult-onset MDS and in certain inherited marrow failure syndromes, apoptosis is increased and is mediated mainly through activation of the Fas pathway. It is unclear whether the various myelodysplastic disorders share the same apoptosis pathways. I investigated apoptosis pathways in a patient with refractory cytopenia with ring sideroblasts associated with congenital 4p deletion to determine the mechanism for bone marrow failure. methods: Marrow cells and lymphoblast cell lines generated from peripheral blood were analyzed for apoptosis and protein expression by flow cytometry, Western blot, and confocal microscopy, either directly or after gamma irradiation (15 G). Cell viability after treatment with inhibitors of specific apoptosis pathways was also determined. RESULTS: Compared to controls, the patient's marrow and lymphoblastoid cells showed significantly higher apoptosis rates and activation of caspase-3. Investigation of the mitochondrial apoptosis pathway showed a consistent pro-apoptosis profile, namely, upregulation of Bax, Bax-alpha, cytochrome c, and Apaf1, and low bcl-2. Differences between the patient's and the normal cells were further accentuated after irradiation; p53 expression was strikingly higher in the patient only after irradiation. In contrast, Fas and FADD expression on the patient's and the control's cells were comparable. Addition of caspase 3 or caspase 9 inhibitors markedly increased patient cell viablity, but blocking anti-Fas antibody did not. CONCLUSION: The ineffective hematopoiesis in this case is explained by increased apoptosis and is linked to hyperactivation of the mitochondrial cell death machinery and not to the Fas pathway, which might be secondary to an intramitochondrial defect. This information is crucial because the development of anti-apoptotic agents for the treatment of MDS may not be universally efficacious and should target the specific derangement.
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ranking = 1.625
keywords = apoptosis
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