UMLS:C0026986 - FACTA Search

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

A specific stain using violet polymethine dye (VPM stain) for megakaryocytes was first developed by Kass (1995). We have modified this method for practical use in bone marrow specimens. The modified VPM stain labels megakaryocytes very well, while other marrow cells are poorly colorized. This staining procedure was more stable, and its color intensity was finer and clearer than the original. Using this stain, morphologic classification of megakaryocytes in bone marrow specimens from 11 normal and 8 myelodysplastic syndrome (MDS) patients was performed. Many megakaryocytes observed in MDS patients were juvenile compared with normal subjects according to their morphology. Blasts from acute megakaryoblastic leukemia (M7) and from a megakaryoblastic cell line (Mo7e) were also clearly stained with our method. This staining method is practical and very useful for rapid identification of megakaryocyte distribution and morphology.
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PMID:A practical quick staining method using hydrochloric acid-fast metachromatic dye for megakaryocytes. 1084 19

The objectives of this study were to expand on recent observations that have suggested decreased thrombopoietin receptor (c-Mpl) expression in megakaryocytes of patients with polycythemia vera (PV) and agnogenic myeloid metaplasia (AMM). We applied an immunoperoxidase method with anti-c-Mpl antibody to 55 bone marrow sections from previously untreated patients with chronic myeloproliferative disorder (CMPD) or myelodysplastic syndrome (MDS). These included 8 patients with PV, 15 with AMM, 9 with essential thrombocythemia, 5 with chronic myelocytic leukemia, 9 with the 5q-syndrome and 9 with MDS with fibrosis. The findings were compared with those in four patients with reactive erythrocytosis (RE), six with immune thrombocytopenic purpura (ITP) and five normal controls. Staining intensity (SI) was moderate to strong both in normal controls and in patients with RE or ITP. In contrast, SI was weak in variable proportions of the megakaryocytes in every one of the aforementioned clonal myeloid disorders. The staining pattern (SP) was relatively uniform in MDS and heterogeneous in CMPD. Neither SI nor SP was significantly correlated with certain clinical or laboratory parameters. We concluded that altered megakaryocyte c-Mpl expression may be a nonspecific phenomenon in various subtypes of both CMPD and MDS. However, the characteristic staining patterns may complement the morphological distinction between clonal and reactive myeloproliferation.
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PMID:Megakaryocyte c-Mpl expression in chronic myeloproliferative disorders and the myelodysplastic syndrome: immunoperoxidase staining patterns and clinical correlates. 1100 52

We studied both serum-free colony-forming unit-megakaryocyte (CFU-meg) numbers and serum thrombopoietin (TPO) levels in 14 patients with aplastic anemia (AA), 37 patients with myelodysplastic syndromes (MDS) and 23 patients with idiopathic thrombocytopenic purpura (ITP) to assess thrombopoiesis in these thrombocytopenic disorders. The mean CFU-meg numbers were lower in AA and MDS patients (10.7 +/- 11.4 and 42.3 +/- 58.5/10(5) BMLD cells) than in healthy controls (103.1 +/- 57.3/10(5) BMLD cells) (P < 0.0001 and P= 0.0053, respectively), although they were distributed variably in MDS. ITP patients showed higher CFU-meg numbers (223.2 +/- 143.5/10(5) BMLD cells) (P= 0.017). The mean TPO concentrations were higher in both AA (986.8 +/- 500.8 pg/ml) and MDS patients (838.2 +/- 639.1 pg/ml) than in healthy controls (80.7 +/- 38.8 pg/ml) (P < 0.0001), although they were distributed from high to low in MDS. ITP patients showed a slight elevation of TPO (123.1 +/- 55.3 pg/ml) P = 0.0106). The TPO levels was inversely correlated to both platelet counts and CFU-meg numbers (correlative coefficient (CC): -0.719 and -0.682, P < 0.0001) in AA, but not in ITP. In MDS, the inverse correlation to TPO was stronger in CFU-meg (CC: -0.678, P < 0.0001) than in platelet counts (CC: -0.538, P = 0.0014), suggesting that CFU-meg plays an important role in regulating TPO production in this heterogenous disorder. CFU-meg and TPO may provide useful information for understanding thrombopoiesis of MDS, especially for application of TPO.
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PMID:Colony-forming unit-megakaryocyte (CFR-meg) numbers and serum thrombopoietin concentrations in thrombocytopenic disorders: an inverse correlation in myelodysplastic syndromes. 1102 50

Thrombopoietin (TPO), a major cytokine involved in megakaryocystopoiesis/thrombopoiesis, may be effective for the treatment of thrombocytopenia associated with myelodysplastic syndromes (MDS). We reviewed the available data relating to the therapeutic potential of TPO for MDS and found the following. The endogenous TPO level is elevated in MDS patients, especially in those with refractory anemia (RA). In RA patients, but not in patients with RA with excess blasts (RAEB) or RAEB in transformation (RAEB-t), both the platelet and megakaryocyte counts correlate inversely with the endogenous TPO level. This scenario indicates that the physiological mechanism for regulating the endogenous TPO level is conserved, at least in part, in RA patients. The number of TPO receptors (TPO-R) expressed on platelets and CD41+ and/or CD34+ cells in MDS is reduced to nearly half the number present in normal subjects. This is consistent with the finding that TPO-induced in vitro megakaryocytopoiesis is not uniformly observed in MDS. Meanwhile, in some patients with RAEB, RAEB-t, or chronic myelomonocytic leukemia, blasts have the TPO-R mRNA and probably TPO-R protein. This fact may explain the lack of correlation between the endogenous TPO level and the platelet and megakaryocyte counts in RAEB and RAEB-t and suggests that TPO may induce blast proliferation in some cases. These findings may be of use when designing a clinical trial of TPO for MDS.
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PMID:Thrombopoietin and myelodysplastic syndromes. 1103 65

It has previously been shown that patients with aplastic anemia (AA) have a stem cell defect both of proliferation and differentiation. This has been shown by long-term bone marrow (BM) culture, long-term initiating cell assays, and committed progenitor assays. We present, for the first time, data on megakaryocyte (Mk) colony formation from purified BM CD34(+) cells from patients with AA. The results are compared with those from normal controls and from patients with paroxysmal nocturnal hemoglobinuria (PNH) and the myelodysplastic syndromes (MDSs). Those treated for AA had previously received immunosuppression (antithymocyte globulin and/or cyclosporin). No patients had received bone marrow transplantation. A total of 13 AA patients (five untreated, eight treated), six PNH, six MDS, and 13 normal donors were studied. BM CD34(+) cells were purified by indirect labeling and then cultured in a collagen-based Mk assay kit (MegaCult-C, StemCell Technologies). The cultures were fixed on day 12, and the Mk colonies were identified by the alkaline phosphatase anti-alkaline phosphatase technique using the monoclonal antibody CD41 (GP IIb/IIIa). The slides were scored for Mk colony-forming units (CFU-Mks) (3-20 and >20 cells), Mk burst-forming units (BFU-Mks) (>50 cells), and mixed colonies. The results show that total Mk colony formation in AA was significantly lower than in normal donors (p<0.0001), both in untreated patients/nonresponders to treatment (p = 0.0001) and in complete/partial responders (p<0.002). There was no significant difference in Mk colony formation in treated and untreated patients (p = 0.05). Patients with AA had a lower total colony formation than PNH patients (p = 0.0002). PNH patients exhibited lower colony formation than normal controls (p = 0.03), as shown by MDS patients, although the considerable number of variables resulted in a lack of statistically significant difference from normal controls (p = 0.2). We have now shown that Mk colony formation from purified BM CD34(+) cells is significantly reduced, supporting previous evidence that AA results from a stem cell defect.
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PMID:In vitro proliferation and differentiation of megakaryocytic progenitors in patients with aplastic anemia, paroxysmal nocturnal hemoglobinuria, and the myelodysplastic syndromes. 1107 31

Thrombopoietin (TPO) is primarily produced by hepatocytes and regulates the production and differentiation of megakaryocytes and platelets in the bone marrow. The endogenous TPO level is increased when the megakaryocyte count is low, and high in aplastic anaemia and after myeloablative chemotherapy. TPO is cloned and manufactured by a recombinant technique for clinical use. Treatment with recombinant human TPO (rhTPO) after intensive chemotherapy may reduce the need for platelet transfusions. Administration of granulocyte colony-stimulating factor in combination with rhTPO has enhanced the mobilisation and harvest product of haematopoietic stem cells. Whether rhTPO is effective in the treatment of the myelodysplastic syndrome, aplastic anaemia, and other conditions with bone marrow insufficiency (including AIDS) is not yet known. In liver cirrhosis, the endogenous TPO level rapidly increases after liver transplantation. Accordingly, substitution of rhTPO may be indicated in advanced liver failure complicated by thrombocytopenia and bleeding.
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PMID:[Clinical use of recombinant human thrombopoietin. Status and perspectives]. 1136 Mar 68

RAS mutations are one of the most frequent molecular abnormalities associated with myeloid leukemia and preleukemia, yet there is a poor understanding of how they contribute to the pathogenesis of these conditions. Here, we describe the consequences of ectopic mutant N-Ras (N-Ras*) expression on normal human erythropoiesis. We show that during early (erythropoietin [EPO]-independent) erythropoiesis, N-Ras* promoted the amplification of a phenotypically primitive but functionally defective subpopulation of CD34(+) erythroblasts. N-Ras* also up-regulated the expression of megakaryocyte antigens on human erythroblasts. Although early erythroblasts expressing N-Ras* were able to respond to erythropoietin and generate mature progeny, this occurred with greatly reduced efficiency, probably explaining the poor colony growth characteristics of these cells. We further report that this oncogene promoted the expression and activation of protein kinase C (PKC) and that the effects of N-Ras* on erythropoiesis could be abrogated or attenuated by inhibition of PKC. Similarly, the effects of this oncogene could be partially mimicked by treatment with PKC agonist. Together, these data suggest that expression of N-Ras* is able to subvert the normal developmental cues that regulate erythropoiesis by activating PKC. This gives rise to phenotypic and functional abnormalities commonly observed in preleukemia, suggesting a direct link between RAS mutations and the pathogenesis of preleukemia.
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PMID:Protein kinase C mediates mutant N-Ras-induced developmental abnormalities in normal human erythroid cells. 1239 54

Thrombocytopenia is a common medical problem for which the main treatment is platelet transfusion. Given the increasing use of platelets and the declining donor population, identification of a safe and effective platelet growth factor could improve the management of thrombocytopenia. Thrombopoietin (TPO), the c-Mpl ligand, is the primary physiologic regulator of megakaryocyte and platelet development. Since the purification of TPO in 1994, 2 recombinant forms of the c-Mpl ligand--recombinant human thrombopoietin (rhTPO) and pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF)--have undergone extensive clinical investigation. Both have been shown to be potent stimulators of megakaryocyte growth and platelet production and are biologically active in reducing the thrombocytopenia of nonmyeloablative chemotherapy. However, neither TPO has demonstrated benefit in stem cell transplantation or leukemia chemotherapy. Other clinical studies have investigated the use of TPO in treating chronic nonchemotherapy-induced thrombocytopenia associated with myelodysplastic syndromes, idiopathic thrombocytopenic purpura, thrombocytopenia due to human immunodeficiency virus, and liver disease. Based solely on animal studies, TPO may be effective in reducing surgical thrombocytopenia and bleeding, ex vivo expansion of pluripotent stem cells, and as a radioprotectant. Ongoing and future studies will help define the clinical role of recombinant TPO and TPO mimetics in the treatment of chemotherapy- and nonchemotherapy-induced thrombocytopenia.
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PMID:Recombinant human thrombopoietin: basic biology and evaluation of clinical studies. 1241 15

There are several common themes that are emerging from our expanding knowledge about the inherited bone marrow failure syndromes. Patients have a spectrum of birth defects, which are relatively characteristic for each syndrome. but overlap in features such as poor growth. radial ray anomalies, and involvement of skin, eyes, renal, cardiac, skeletal, and other organs. Within each syndrome the composition and severity of the physical phenotype varies widely, and it may require the astute observer to make the correct diagnoses in the milder cases. There is also a wide spectrum to the hematologic picture. These range from single cytopenias such as DBA, SCN, and TAR, which do not develop pancytopenia, to SD and Amega patients who begin with deficiency of a specific single lineage, but evolve to aplastic anemia, to patients with FA or DC, who may present with a deficiency of any one of the cell lines, but almost inevitably end up with full-blown aplastic anemia. Acute myeloid leukemia has been observed in FA, DBA, DC, SD, SCN, and Amega, although not yet in TAR patients. MDS has also been reported in all of the same disorders as AML, although whether it is a preleukemic condition or an independent bone marrow dyspoiesis is not yet clear. Solid tumors are also now appearing in patients whose underlying disease involves hematopoiesis and physical development. These tumors occur at much younger ages than in the general population, in patients who do not appear to have the usual risk factors, and have patterns that are characteristic to the syndrome, such as head and neck and gynecologic cancers in FA and DC, and osteogenic sarcomas in DBA. The other syndromes have not yet been reported to have a propensity for solid tumors. Several genes have been identified that are mutant in some of the syndromes, although the pathophysiology is still not entirely clear. The inheritance patterns include X-linked recessive, autosomal dominant, autosomal recessive, and even mitochondrial. The FA gene products appear to cooperate, and are important in the pathways involved in response to DNA damage. However, the role of this pathway in developmental defects, hematopoietic failure, and the specific malignancies in FA is not fully elucidated. The DC gene products are important for maintenance of telomere length, which may have relevance to development of aplastic anemia and malignancies, but the relation to the physical phenotype is less apparent. The role of mutations in c-mpl in Amega is more straightforward. since the gene codes for the receptor for thrombopoietin. which is the hormone required for megakaryocyte and platelet development; patients with mutant c-mpl do not have birth defects. The role of mutations in RPS19 in erythropoiesis or developmental defects in DBA patients is not obvious, and the increased frequency of osteogenic sarcomas suggests that at least that subset of patients may have a mutant tumor suppressor gene (such as p53, the mutant gene in Li-Fraumeni syndrome) [68]. Although patients with SCN have mutations in neutrophil elastase, patients with similar mutations may have relatively benign cyclic neutropenia, or may even have normal neutrophil levels [69,70]. The mitochondrial gene deletions in Pearson's Syndrome result in variable degrees of acidosis, and varied organ involvement due to heteroplasmy. Thus, the disorders included under the rubric "inherited bone marrow failure syndromes" have clinical. hematologic, oncologic, and genetic diversity.
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PMID:Bone marrow failure syndromes in children. 1243 Jun 21

Biological and clinical significance of growth pattern of hematopoietic progenitors were investigated in 117 patients with primary myelodysplastic syndromes (MDSs) at referral. Abnormal (i.e., "leukemic" or absent) growth of GM colonies (CFU-GM) and GM clusters was found in 47% of patients with "advanced" MDS (RAEB, RAEB-t, and CMML) and in 15% of "low-risk" (RA/RARS) patients. In vitro erythropoiesis was decreased in most of the patients, with significantly lower number of BFU-E in "advanced" MDS than in RA/RARS patients. Megakaryocyte progenitors (CFU-MK) were very low or absent in almost all the patients, regardless of the FAB type. Significant correlation was demonstrated between the number of BFU-E and hemoglobin concentration and between number of CFU-MK and platelet count. Growth capacity of GM progenitors appears to be in proportion to "myeloproliferative" capacity of the malignant clone. T-cell depletion had no influence on growth capacity of hematopoietic progenitors, nor did colony growth respond in a dose-dependent manner to different concentrations of LCM. Growth capacity of MDS hematopoietic progenitors was independent of Bournemouth score, of the presence and type of cytogenetic abnormality, and of the expression of CD95 and caspase-3 antigens on bone marrow cells. However, in patients with "abnormal" growth of GM progenitors, CD34 antigen expression was significantly higher than in patients with "normal" growth. "Abnormal" GM growth was found to be independently predictive regarding the survival and the risk for AML development. In contrast, the prognostic value of erythroid and megakaryocyte cultures was found to be limited.
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PMID:Biological and clinical significance of clonogenic assays in patients with myelodysplastic syndromes. 1251 19

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