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)

The minichromosome maintenance (Mcm) and Cdc6 proteins are important regulators of eucaryotic DNA replication. In most normal tissues, a similar proportion of cells express Mcm-2 and Ki-67. The present study showed that in both normal and abnormal states, the proportion of megakaryocytes expressing Mcm-2 is roughly seven times as many as those that express Ki-67. This is likely to be related to the process of endomitosis and endoreduplication. We also demonstrated that a significantly lower proportion of megakaryocytes in myelodysplastic syndrome express Mcm-2. These findings provide new insights into megakaryocyte biology.
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PMID:The expression of minichromosome maintenance protein-2 in normal and abnormal megakaryocytes and comparison with the proliferative marker Ki-67. 1628 41

To investigate the morphological changes of megakaryocytes with nuclear extrusion and nucleocytoplasmic separation, the morphological characteristics of megakaryocytes in peripheral blood films, bone marrow smears, and bone marrow biopsies from 4 newly diagnosed patients with primary myelofibrosis (PMF), myelodysplastic syndrome (MDS), myeloblastic leukemia with maturation (M(2)) and erythroleukemia (M(6)) were studied by using light microscope. The results showed that many kinds of dysmegakaryocytes were observed in bone marrow smears of 4 cases, while in case A (PMF) and case D (M(6)) micromegakaryocytes were ripped apart; in case B (MDS) and case C (M(2)) megakaryocytes were accompanied by nuclear extrusion or nucleocytoplasmic separation, and their bodies were large or giant, the part of nucleus separated from their body and little cytoplasm remained as micromegakaryocytes. The nucleocytoplasmic separation could be displayed by immunocytochemistry stain. It is concluded that the phenomenon of nuclear extrusion and nucleocytoplasmic separation in megakaryocytes suggested the process that dispersed multinuclear releasing towards surround or even totally left the cell body during the megakaryocyte maturation. It also showed that the micromegakaryocytes may be the result of nucleocytoplasmic separation or splittings from multi-separated nucleus.
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PMID:Morphological study on the megakaryocytes with nuclear extrusion and nucleocytoplasmic separation in four cases. 1640 85

Acute leukemia of megakaryocyte lineage (AML-7) is a rare entity defined by a blastic proliferation of which a part (>or= 50%) is represented by megakaryoblasts. We report the case of a 95 year old woman presenting a AML-7 secondary to a myelodysplastic syndrome (MDS), that represents an unusual form of MDS acutisation.
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PMID:[Acute megakaryoblastic leukemia (AML-7) in a woman of 95 years]. 1655 30

Thrombopoietin (TPO) serum levels were quantified in patients with myelodysplastic syndromes using an ELISA test for TPO. We found that TPO levels were significantly elevated in the whole group of patients as compared with normal healthy donors (521.9 75.3 pg/ml vs 160.1 19.6 pg/ml; P = 0.011). TPO serum levels were inversely correlated with the megakaryocyte mass in both the RA/RARS and RAEB/RAEBt subgroups ( P = 0.012 and P = 0.031, respectively). Two subsets of patients with a possible dysregulation of TPO production were identified.
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PMID:Elevated thrombopoietin serum concentrations in myelodysplasias. 1679 51

Platelet production requires compartmentalized caspase activation within megakaryocytes. This eventually results in platelet release in conjunction with apoptosis of the remaining megakaryocyte. Recent studies have indicated that in low-risk myelodysplastic syndromes (MDS) and idiopathic thrombocytopenic purpura (ITP), premature cell death of megakaryocytes may contribute to thrombocytopenia. Different cell death patterns have been identified in megakaryocytes in these disorders. Growing evidence suggests that, besides apoptosis, necrosis and autophagic cell death, may also be programmed. Therefore, programmed cell death (PCD) can be classified in apoptosis, a caspase-dependent process, apoptosis-like, autophagic and necrosis-like PCD, which are predominantly caspase-independent processes. In MDS, megakaryocytes show features of necrosis-like PCD, whereas ITP megakaryocytes demonstrate predominantly characteristics of apoptosis-like PCD (para-apoptosis). Triggers for these death pathways are largely unknown. In MDS, the interaction of Fas/Fas-ligand might be of importance, whereas in ITP antiplatelet autoantibodies recognizing common antigens on megakaryocytes and platelets might be involved. These findings illustrate that cellular death pathways in megakaryocytes are recruited in both physiological and pathological settings, and that different forms of cell death can occur in the same cell depending on the stimulus and the cellular context. Elucidation of the underlying mechanisms might lead to novel therapeutic interventions.
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PMID:Megakaryocytic dysfunction in myelodysplastic syndromes and idiopathic thrombocytopenic purpura is in part due to different forms of cell death. 1699 Jul 74

Myelodysplastic syndromes (MDS) comprise a collection of hematologic disorders characterized by deficiencies in peripheral blood cells, particularly those of the granulocyte, erythrocyte, and megakaryocyte lineages. A number of chromosomal abnormalities are associated with the development of MDS, including mutations involving chromosomes 7q, 5q, 20q, 6q, 11q, and 13q. Until recently, supportive care or allogeneic stem cell transplantation (ASCT) were the only available treatment options for this disease. ASCT is potentially curative but poses high mortality risk in the predominantly elderly MDS population. Supportive care options traditionally included blood transfusions and antibiotics, with the goal of reducing morbidity from ineffective hematopoiesis and improving quality of life. This approach has been enhanced by treatment with various growth factors aimed at stimulating blood cell production, including erythropoietin and granulocyte colony-stimulating factor. These growth factors, along with the use of iron chelation therapy to counteract the iron overload that can develop after frequent transfusions, have recently been shown to have the potential to prolong survival in MDS patients. In addition to these advances in supportive care, three new agents have been approved for the treatment of MDS in the past 3 years. Lenalidomide, azacitidine, and decitabine all target molecular processes underlying the pathophysiology of MDS and have shown considerable activity and, more recently, potential survival benefits in various subgroups of patients. Considerable changes in the treatment of MDS are expected in coming years as these and other novel agents are tested alone and in combination with one another to further refine the treatment paradigm for MDS.
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PMID:Evaluating new treatment options for MDS. 1818 91

Abnormal nuclear megakaryocytic staining for phospho-STAT5 (pSTAT5) correlates with JAK2 V617F mutational status in non-chronic myelogenous leukemia chronic myeloproliferative disorders. However, a proportion of wild-type JAK2 non-chronic myelogenous leukemia chronic myeloproliferative disorders cases also demonstrate this abnormal pSTAT5 expression pattern. We report a patient with a JAK2 V617F-negative myeloproliferative/myelodysplastic syndrome who had abnormal megakaryocytic pSTAT5 expression and a MPL W515L mutation. The patient was a 71-year-old man with anemia and thrombocythemia on laboratory examination. His peripheral blood smear demonstrated occasional dysplastic neutrophils. Bone marrow biopsy revealed hypercellular marrow with features consistent with myeloproliferative/myelodysplastic syndrome. Immunohistochemistry for pSTAT5 showed abnormal nuclear megakaryocyte positivity. Cytogenetic analysis revealed a normal karyotype, fluorescence in situ hybridization for BCR-ABL was negative, and JAK2 genotyping demonstrated wild-type JAK2. However, MPL genotyping showed a MPL W515L mutation. Abnormal nuclear megakaryocytic staining for pSTAT5 expression, previously associated with the JAK2 V617F mutation, is also associated with MPL W515L, likely reflecting activation of the JAK-STAT signaling pathway.
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PMID:Phospho-STAT5 expression pattern with the MPL W515L mutation is similar to that seen in chronic myeloproliferative disorders with JAK2 V617F. 1847 30

The transcription factor RUNX-1 plays a key role in megakaryocyte differentiation and is mutated in cases of myelodysplastic syndrome and leukemia. In this study, we purified RUNX-1-containing multiprotein complexes from phorbol ester-induced L8057 murine megakaryoblastic cells and identified the ets transcription factor FLI-1 as a novel in vivo-associated factor. The interaction occurs via direct protein-protein interactions and results in synergistic transcriptional activation of the c-mpl promoter. Interestingly, the interaction fails to occur in uninduced cells. Gel filtration chromatography confirms the differentiation-dependent binding and shows that it correlates with the assembly of a complex also containing the key megakaryocyte transcription factors GATA-1 and Friend of GATA-1 (FOG-1). Phosphorylation analysis of FLI-1 with uninduced versus induced L8057 cells suggests the loss of phosphorylation at serine 10 in the induced state. Substitution of Ser10 with the phosphorylation mimic aspartic acid selectively impairs RUNX-1 binding, abrogates transcriptional synergy with RUNX-1, and dominantly inhibits primary fetal liver megakaryocyte differentiation in vitro. Conversely, substitution with alanine, which blocks phosphorylation, augments differentiation of primary megakaryocytes. We propose that dephosphorylation of FLI-1 is a key event in the transcriptional regulation of megakaryocyte maturation. These findings have implications for other cell types where interactions between runx and ets family proteins occur.
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PMID:Differentiation-dependent interactions between RUNX-1 and FLI-1 during megakaryocyte development. 1947 Jul 63

A boy 3 years 7 months old with thrombocytopenia and history of intracranial hemorrhage who underwent bone marrow transplantation is presented. He was refractory to steroids, immunoglobulin G, vincristine, azathioprine, cyclosporine A, interleukin-11, chemotherapy, and splenectomy. Idiopathic thrombocytopenic purpura was excluded by light /electron microscopic and flow cytometric findings; the diagnosis of refractory cytopenia, a subgroup of pediatric myelodysplastic syndrome, was made. Naked megakaryocyte nuclei were 55.38 +/- 28.2% vs. 31.67 +/- 23.22% of all megakaryocytes in the patient and the control group of 9 patients with idiopathic thrombocytopenic purpura, respectively (p = .016). The posttransplatation course was complicated by delayed platelet engraftment, bronchiolitis obliterans associated with pneumocystis carinii pneumonia, which resolved completely.
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PMID:Excessive naked megakaryocyte nuclei in myelodysplastic syndrome mimicking idiopathic thrombocytopenic purpura: a complicated pre- and post-transplantation course. 1965 88

Thrombopoietin (TPO) is the physiologic regulator of platelet production and works by binding to its receptor on megakaryocyte precursor cells, thereby activating a large number of antiapoptotic and cell maturation pathways. "First-generation" recombinant forms of TPO were developed over a decade ago and were found to increase the platelet count in patients undergoing nonmyeloablative chemotherapy, in patients with immune thrombocytopenic purpura (ITP) and myelodysplasia, as well as in platelet apheresis donors. Thrombopoietin did not improve platelet counts in patients undergoing stem cell transplantation or acute leukemia induction. Further development ended when antibodies formed against one of the recombinant proteins. Subsequently, 2 "second-generation" TPO mimetics have been developed and are entering clinical practice: romiplostim and eltrombopag. Romiplostim is an injectable peptide TPO mimetic that activates the TPO receptor just like native TPO. Eltrombopag is an oral nonpeptide TPO mimetic that activates the TPO receptor by binding to a different region of the TPO receptor that does not compete with TPO binding. Both increased the platelet counts in healthy subjects and in over two thirds of patients with ITP both before and after splenectomy; responses were maintained for at least 1 year. Romiplostim and eltrombopag are now US Food and Drug Administration approved for the second-line treatment of patients with ITP. Adverse events have been few, but long-term assessment for reticulin formation, increased bone marrow blasts, and thromboembolism is ongoing. Studies are under way to assess the efficacy of these drugs in the treatment of other thrombocytopenic disorders associated with chemotherapy, myelodysplasia, and chronic hepatitis.
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PMID:New thrombopoietic growth factors. 1977 63


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