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 c-mpl gene encodes a member of the hematopoietic cytokine receptor superfamily. This gene was discovered through the study of a murine retrovirus which induces an acute myeloproliferative syndrome in mice. MPLV (for myeloproliferative leukemia virus) has transduced a truncated and constitutively activated form of the c-mpl receptor chain. The c-mpl ligand is unknown, but recent data indicate that it could specifically regulate thrombocytopoiesis. This review focuses on the expression of the c-mpl gene in a large series of human hematopoietic pathologies by Northern blot analysis. Barely detectable transcript levels were detected in normal bone marrow (BM) and in BM samples from chronic myeloproliferative disorders, plasmocytoma, Burkitt lymphoma or acute lymphoid leukemia. In contrast, high levels of c-mpl expression were detected in 45% of acute myeloid leukemia (AML). No correlation was found between c-mpl expression and the French-American-British classification subtype of AML. However c-mpl expression correlated with CD34 expression, and unfavorable cytogenetic abnormalities, defining a subgroup of AML with a low rate of complete remission. In myelodysplasia, c-mpl expression was elevated in 44% of chronic myelomonocytic leukemia (CMML), 42% of refractory anemia with excess myeloblasts (RAEB), and RAEB in transformation to acute leukemia (RAEBt), but not in refractory anemia (RA) and RA with ringed sideroblasts (RARS). In CMML, there was no correlation between c-mpl expression and any prognostic factor tested, nor with the course of the disease. The biologic significance of c-mpl expression in RAEB and RAEBt is probably different.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:c-mpl expression in hematologic disorders. 777 60

The Mpl ligands are a family of closely related hematopoietic growth factors that bind to the thrombopoietin receptor, c-Mpl. In addition to the endogenous Mpl ligand, thrombopoietin, two recombinant Mpl ligands, recombinant thrombopoietin and pegylated megakaryocyte growth and development factor (PEG-MGDF) are under investigation. Endogenous thrombopoietin regulates most of the normal production of platelets but also is essential for the normal development of other lineages. When recombinant thrombopoietin or PEG-MGDF is administered to normal animals or humans, there is a dose-dependent increase in the platelet count but no effect on leukocytes or erythrocytes. When administered following chemotherapy in animal models or humans, Mpl ligands reduce the duration and sometimes the degree of thrombocytopenia. The Mpl ligands also may be effective in reducing the thrombocytopenia of patients with HIV infection, liver disease, myelodysplasia, or after plateletpheresis.
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PMID:In vivo effects of Mpl ligand administration and emerging clinical applications for the Mpl ligands. 920 31

The gene for the thrombopoietin receptor, c-mpl, has been shown to be overexpressed at the mRNA level in acute myeloid leukemia (AML) and myelodysplastic syndrome. A recent study reported c-mpl mRNA overexpression in 60% of a small sample of AML patients, and this overexpression correlates with shorter complete remission but not with karyotype group. We quantified c-mpl protein expression in 107 cases of AML and 24 normal bone marrow and 12 normal peripheral blood samples by using Western blot analysis and radioimmunoassay (RIA). Western blot analysis revealed no detectable level of c-mpl protein in the normal samples, whereas trace amounts were detected by RIA. c-mpl protein expression was increased (> or = twice normal) in 65% of the AML cases. c-mpl protein expression was correlated with cytogenetic groups (P = 0.0009, Kruskal-Wallis test in rejecting the hypothesis that c-mpl expression was the same in different groups). Specifically, patients with favorable cytogenetic groups (t(8;21), inv16, and t(15;17)) had lower c-mpl protein expression (median 1.7 times normal), whereas patients with unfavorable abnormalities (+8, -5 or -7, and del(11)(q23)) and normal cytogenetics had high expression (3.1 and 2.85 times normal, respectively). The findings were the same when only the 61 untreated AML patients were considered. No statistically significant correlation between c-mpl expression and age or antecedent hematologic disorder was found. These results suggest that c-mpl protein overexpression in AML may play a role in the aggressiveness of this disease.
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PMID:Correlation between lower c-mpl protein expression and favorable cytogenetic groups in acute myeloid leukemia. 993 37

Expression of the thrombopoietin receptor, c-mpl, has been recently suggested to represent an adverse prognostic factor in myelodysplasia and acute myeloid leukemia (AML). To further evaluate this putative correlation, we assessed the c-mpl mRNA expression in blast samples of 53 AML patients. Overall, c-mpl mRNA expression was observed in 27 (51%) patients. No significant difference between c-mpl(+) and c-mpl(-) patients was found with respect to established prognostic factors such as age (50 vs. 53 years) or karyotype, whereas a significant correlation was observed between c-mpl and CD34 expression (P = 0.026). Among 40 patients who completed standard-/high-dose cytarabine-containing induction/consolidation treatment and were evaluable for treatment response, a higher complete remission (CR) rate was achieved in c-mpl- than in c-mpl(+) patients (95 vs. 68%; P = 0.026). Upon multivariate analysis, this relationship was independent from CD34 expression. CR duration was not significantly longer in c-mpl(-) than in c-mpl(+) patients (median: 14 vs. 10 months, P = 0.262). In conclusion, our data strongly support the previously suggested notion that c-mpl expression is of prognostic relevance for CR induction in de novo AML patients, and suggest determination of c-mpl expression within larger prospective studies in the attempt to develop risk-adapted AML treatment strategies.
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PMID:Analysis of thrombopoietin receptor (c-mpl) mRNA expression in de novo acute myeloid leukemia. 1078 62

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

Mutations in the genes of hematopoietic growth factor receptors as a cause of congenital cytopenia, such as congenital amegakaryocytic thrombocytopenia (CAMT) or severe congenital neutropenia (CN), are discussed. There are striking differences in the relevance of receptor mutations in these diseases. CAMT is a rare disease characterized by severe hypomegakaryocytic thrombocytopenia during the first years of life that develops into pancytopenia in later childhood. In patients with CAMT, we found inherited mutations in c-mpl, the gene coding for the thrombopoietin receptor, in 8 out of 8 cases. The type of mutation seems to correlate with the clinical course seen in the patients. Functional studies demonstrated defective thrombopoietin (TPO) reactivity in hematopoietic progenitor cells and platelets in CAMT patients. CN is a group of hematopoietic disorders characterized by profound, absolute neutropenia due to a maturation arrest of myeloid progenitor cells. About 10% of all patients develop secondary MDS/leukemia. The malignant progression is associated with acquired nonsense mutations within the G-CSF receptor gene that lead to the truncation of the carboxy-terminal cytoplasmic domain of the receptor protein involved in maturation of myeloid progenitor cells. This seems to be one important step in leukemogenesis in CN patients. CAMT is caused by inherited mutations in c-mpl, the gene for the thrombopoietin receptor, which lead to reduced or absent reactivity to TPO. In contrast, mutations in the G-CSF receptor in CN are acquired and are most probably connected with progression of the neutropenia into MDS/leukemia as a result of a loss of differentiation signaling.
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PMID:Implications of mutations in hematopoietic growth factor receptor genes in congenital cytopenias. 1145 19

Amgen Inc is developing AMG-531, a peptibody that binds to the thrombopoietin receptor Mpl, for the potential treatment of immune thrombocytopenic purpura (ITP), chemotherapy-induced thrombocytopenia (CIT) and thrombocytopenia in myelodysplastic syndrome (MDS). Results of the US phase III trial in ITP are expected to be available in the second half of 2006, while a phase II trial in CIT is still underway. A Japanese phase II ITP study has been initiated, as has a phase II trial of MDS patients in the US and France.
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PMID:Drug evaluation: AMG-531 for the treatment of thrombocytopenias. 1700 62

Platelets play a pivotal role in maintaining hemostatic competence. Thrombocytopenia, irrespective of its etiology, is associated with a risk for bleeding. Treatment modalities for chronic idiopathic thrombocytopenic purpura (ITP) are numerous, but the response is variable, often disappointing and associated with high risks. Better understanding of the pathophysiology of chronic ITP, indicating impaired platelet production rather than simply increased turnover, led to clinical trials aimed at increasing platelet production with thrombopoietin receptor agonists. To date, two compounds have been investigated extensively, romiplostim (AMG-531, Nplate) and eltrombopag (SB-497115, Promacta, Revolade). The success of this treatment further paved the way for evaluating its efficacy in raising platelet counts in hepatitis C virus (HCV)-related infection and myelodysplastic syndrome. Although there is less experience in hepatitis C than in chronic ITP, preliminary data are highly promising. This review will focus on the experience gained with eltrombopag in chronic ITP and HCV-related thrombocytopenia.
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PMID:Eltrombopag in chronic idiopathic thrombocytopenic purpura and HCV-related thrombocytopenia. 1934 29

Myelodysplastic syndromes (MDS) are a group of heterogeneous clonal stem cell (SC) disorders that mainly affect the elderly population. They are characterized by ineffective hematopoiesis which results in quantitative and qualitative cellular defects and high incidence of leukemic transformation. Recent advances in MDS research have led to the development of novel agents which appears to improve remission rates and survival when compared to best supportive care. Currently azacitidine, decitabine, and lenalidomide are approved by the US FDA for the treatment of MDS, while the activity of other novel agents such as histone deacetylase inhibitors, farnesyl-transferase inhibitors, novel thrombopoietic agents, and anti-angiogenesis molecules is under evaluation. Erythropoietin-stimulating agents, iron chelating therapy and thrombopoietin receptor ligands may also improve quality of life and possibly prolong survival in MDS patients. The only treatment modality that can achieve long-term survival is the allogeneic SC transplantation which is given only in selected patients. Moreover the heterogeneity of MDS and the patient's advanced age and co-morbidity are significant factors besides cytogenetics, IPSS and WPSS that should be taken into account during the decision-making process. Therefore clinicians should treat patients with MDS on an individual basis aiming the increase of the response rates and the decrease of treatment-associated toxicities. This can only be achieved through the better understanding of the MDS subgroups. If we can better define MDS subgroups we will be able to identify patients who will benefit from the incorporation of the novel agents, as monotherapy or in combinations regimens along with supportive care.
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PMID:Incorporating novel agents in the treatment of myelodysplastic syndromes. 1965 66

Thrombocytopenia is a frequent symptom and clinical challenge in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Eltrombopag is a small molecule thrombopoietin receptor agonist that might be a new option to treat thrombocytopenia in these diseases, provided that it does not stimulate malignant hematopoiesis. In this work, we studied the effects of Eltrombopag on proliferation, apoptosis, differentiation, colony formation, and malignant self-renewal of bone marrow mononuclear cells of patients with AML and MDS. Malignant bone marrow mononuclear cells did not show increased proliferation, or increased clonogenic capacity at concentrations of Eltrombopag ranging from 0.1 to 30 microg/mL. On the contrary, we observed a moderate, statistically nonsignificant (P = .18), decrease of numbers of malignant cells (mean, 56%; SD, 28%). Eltrombopag neither led to increased 5-bromo-2-deoxyuridine incorporation, decreased apoptosis, an increase of malignant self-renewal, nor enhanced in vivo engraftment in xenotransplantations. Furthermore, we found that Eltrombopag was capable of increasing megakaryocytic differentiation and formation of normal megakaryocytic colonies in patients with AML and MDS. These results provide a preclinical rationale for further testing of Eltrombopag for treatment of thrombocytopenia in AML and MDS.
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PMID:Effect of the nonpeptide thrombopoietin receptor agonist Eltrombopag on bone marrow cells from patients with acute myeloid leukemia and myelodysplastic syndrome. 1971 May 4


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