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

To evaluate the hematologic effects of recombinant human interleukin-6 (rhIL-6, Escherichia coli, SDZ ILS 969, IL-6), and determine its toxicity profile, we performed a phase I trial of IL-6 in 22 patients with various myelodysplastic syndromes (MDS), platelet counts < 100,000/microL, and < 5% bone marrow (BM) blasts. Patients received one of four doses of IL-6 (1.0, 2.5, 3.75, and 5.0 micrograms/kg/d) as a subcutaneous injection on day 1, followed by a 7-day wash-out period, and then 28 days of IL-6 therapy. Dose-limiting toxicities of fatigue, fever, and elevated alkaline phosphatase were seen at 5.0 micrograms/kg/d; the maximum tolerated dose was 3.75 micrograms/kg/d. All patients experienced at least grade II fever and all had an increase in acute phase proteins. Eight patients (36%) experienced at least a transient improvement in platelet counts; three fulfilled the criteria for response, whereas five others had clinically significant increases that failed to meet response criteria. Various IL-6-related toxicities prevented more than three patients from receiving maintenance therapy. Two of the three patients who received maintenance IL-6 therapy had a persistent increase in platelet counts, during 3 and 12 months of IL-6 therapy, respectively. Laboratory studies indicated that IL-6 increased the frequency of higher ploidy megakaryocytes but did not significantly increase the number of assayable megakaryocytic progenitor cells, suggesting that IL-6 acts as a maturational agent rather than a megakaryocyte colony-stimulating factor. Although IL-6 therapy can promote thrombopoiesis in some MDS patients, its limited activity and significant therapy-related toxicity preclude its use as a single agent in this patient population. Further studies, combining low doses of IL-6 with other hematopoietic growth factors, are underway.
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PMID:A phase I trial of recombinant human interleukin-6 in patients with myelodysplastic syndromes and thrombocytopenia. 753 15

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

A novel long-term cultured interleukin (IL)-3-dependent human myelodysplastic cell line, MDS92, was shown to contain several myeloid-lineage cells such as neutrophils, macrophages, eosinophils, and a small number of megakaryocyte-lineage cells. Therefore this cell line possesses at least bipotential characteristics of myeloid- and megakaryocyte-lineages. Granulocyte colony-stimulating factor clearly promoted the neutrophil alkaline phosphatase activity of MDS92 cells. To the contrary, the incidence and growth of CD41-positive cells were hardly affected by the addition of IL-6, IL-11, c-mpl ligand (thrombopoietin, TPO) or erythropoietin. TPO slightly supported the growth of CD34-positive cell fraction, but not CD41-positive cell fraction of MDS92 cells in combination with IL-3 or Steel factor. This cell line will be a useful tool for the study of MDS stem cells, but the mechanism of commitment of differentiation in MDS stem cells remains unknown.
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PMID:A novel factor-dependent human myelodysplastic cell line, MDS92, contains haemopoietic cells of several lineages. 854 20

The survival, proliferation, differentiation and function of normal hematopoietic cells are negatively and positively controlled by various cytokines. Survival and proliferation of leukemic cells appears to be influenced, at least in vitro, by several cytokines. Among the different hematopoietic cell lineages, megakaryocytopoiesis represents a complex and unique hematopoietic system that is thought to be supported by some well-known cytokines; however, the hypothetical lineage-specific main regulator of platelet production, termed thrombopoietin (TPO) had remained elusive. Recently, characterization of the proto-oncogene c-mpl revealed structural homology with the hematopoietic cytokine receptor superfamily, specific expression on cells of the megakaryocytic lineage and functional involvement in megakaryocytopoiesis. Several groups purified and cloned the MPL ligand. Extensive in vitro and in vivo studies have shown that the MPL ligand has activity in stimulating both megakaryocytopoiesis and platelet production proving that this ligand is the long-sought growth factor TPO itself. The MPL receptor was found at the mRNA and/or protein level in 40-80% of primary acute myeloid leukemia (AML) cases in various series. MPL expression was not limited to certain morphological FAB types, although the highest percentages were seen in the M6 (erythroid) and M7 (megakaryocytic) subclasses. Among the myelodysplastic syndromes (MDS), MPL expression was detected in one third of the cases, in particular in refractory anemia with excess of blasts and chronic myelomonocytic leukemia. Lymphoid malignancies such as acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma (NHL) and myeloma were MPL-negative. Among the large panel of human leukemia-lymphoma cell lines studied, MPL expression occurred predominantly in lines with erythro-megakaryocytic phenotypes. Nearly all primary and continuously cultured non-hematopoietic solid tumor samples were negative for MPL expression. A significant portion of AML cases and of erythroid, megakaryocytic and myeloid leukemia cell lines co-expressed TPO and MPL mRNA transcripts, although no biologically active TPO appeared to be secreted by these cells. In several studies TPO induced in vitro proliferation of 14-37% of primary AML cases, predominantly of the M2 and M7 subtypes. TPO significantly enhanced the cytokine-induced growth of AML cells in a substantial fraction of cases responsive to GM-CSF, IL-3, IL-6 or SCF. While none of 30 growth factor-independent erythro-megakaryocytic leukemia cell lines responded to TPO with increased proliferation, TPO strongly augmented the growth of several constitutively cytokine-dependent cell lines (eg HU-3, M-07e, TF-1) which can be made TPO-dependent and used as bioassays. Neither in primary cells nor in cell lines did TPO appear to induce any signs of morphological, functional or immunological differentiation. Expression of the MPL receptor is not correlated with a proliferative response to TPO. In summary, extensive studies on normal human and animal cells demonstrated the specificity and function of the MPL receptor and proved that its ligand TPO is the major physiological regulator of megakaryocytopoiesis. The data reviewed here document the wide expression of the MPL receptor on AML cells and also suggest some proliferative effects on certain leukemia cells, apparently on non-megakaryocytic AML cells as well. Thus, experimental evidence supports the notion that TPO may contribute, at least in part, to leukemogenesis, especially in combination with other hematopoietic cytokines which is of clinical significance. TPO-responsive cell lines represent powerful tools for such analyses.
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PMID:Thrombopoietin: expression of its receptor MPL and proliferative effects on leukemic cells. 875 57

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

Mpl ligand is a recently cloned haemopoietic growth factor that stimulates megakaryopoiesis in vitro and in vivo. We describe the in vitro effect of a truncated form of Mpl ligand, recombinant human megakaryocyte growth and development factor (rHuMGDF), on megakaryopoiesis in bone marrow from normal subjects and patients with myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). We used both semi-solid and suspension culture techniques to assess the effect of pegylated (PEG) rHuMGDF on megakaryocyte colony growth (CFU-Mk) and on the production of CD61+ cells in 7d suspension cultures. PEG rHuMGDF increased CFU-Mk growth and CD61+ cell production in a dose-dependent fashion in all normal marrows tested. Normal CFU-Mk growth was increased threefold with the addition of 10 ng/ml PEG rHuMGDF to cultures and CD61+ cells were increased 8-10-fold by the same dose. Although increased CFU-Mk growth was only seen in 1/10 AML and 6/16 MDS marrows, CD61+ cell numbers in suspension culture were increased in 9/13 AML and 12/15 MDS samples, responses ranged from very limited to normal magnitude. There was no correlation between platelet count and CFU-Mk number, CD61+ cell number or response to PEG rHuMGDF. We did not find any increased CFU-GM colony or cluster growth in response to PEG rHuMGDF and the CD61+ cells produced in suspension culture had features of megakaryocytic differentiation. These data suggest that PEG rHuMGDF can enhance megakaryocyte proliferation in some patients with MDS and AML, and may have a role in the treatment of thrombocytopenia in these patients.
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PMID:The in vitro effect of pegylated recombinant human megakaryocyte growth and development factor (PEG rHuMGDF) on megakaryopoiesis in normal subjects and patients with myelodysplasia and acute myeloid leukaemia. 935 14

To evaluate the diagnostic value of thrombopoietin (TPO, c-mpl ligand) measurements, and clarify the regulatory mechanisms of TPO in normal and in thrombocytopenic conditions, the plasma TPO concentration was determined in normal individuals (n = 20), umbilical cord blood (n = 40), chronic idiopathic thrombocytopenic purpura (ITP; n = 16), in severe aplastic anaemia (SAA; n = 3), chemotherapy-induced bone marrow hypoplasia (n = 10), myelodysplastic syndrome (MDS; n = 11), and sequentially during peripheral blood progenitor cell transplantation (n = 7). A commercially available ELISA and EDTA-plasma samples were used for the analysis. The plasma TPO concentration in the normals and umbilical cord blood were 52 +/- 12 pg/ml and 66 +/- 12 pg/ml, respectively. The corresponding values in patients with SAA and chemotherapy-induced bone marrow hypoplasia were 1514 +/- 336 pg/ml and 1950 +/- 1684 pg/ml, respectively, and the TPO concentration, measured sequentially after myeloablative chemotherapy and peripheral blood progenitor cell transplantation, was inversely related to the platelet count. In contrast, the plasma TPO recorded in patients with ITP (64 +/- 20 pg/ml) and MDS (68 +/- 23 pg/ml) were only slightly higher than normal levels. In conclusion, TPO levels were significantly elevated in patients in which bone marrow megakaryocytes and platelets in circulation were markedly reduced, whereas TPO levels were normal in ITP patients, and only slightly increased in the MDS patients. These latter patients displayed a preserved number of megakaryocytes in bone marrow biopsies. Our data support the suggestion that megakaryocyte mass affects the plasma TPO concentration. In thrombocytopenic patients a substantially increased plasma TPO implies deficient megakaryocyte numbers. However, TPO measurements do not distinguish between ITP and thrombocytopenia due to dysmegakaryopoiesis, as seen in MDS patients.
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PMID:Plasma thrombopoietin levels in thrombocytopenic states: implication for a regulatory role of bone marrow megakaryocytes. 963 81

Thrombocytopenia is a frequent feature of myelodysplastic syndromes (MDS) that could be improved by the use of recombinant human megakaryocyte growth and development factor (rHuMGDF). Using short-term liquid cultures and progenitor assays, we have found that rHuMGDF stimulated DNA synthesis and potentiated leukemic cluster growth of bone marrow mononuclear cells in 10/38 MDS cases (26%). Cytogenetically malignant colonies were detectable in rHuMGDF-stimulated cultures (n=3) by fluorescence in situ hybridization. rHuMGDF was able to stimulate CFU-MK formation in 45% of the samples tested. Finally, rHuMGDF-induced blast cell proliferation correlated with elevated expression of c-MPL, previously identified as a bad prognosis factor in MDS.
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PMID:Analysis of megakaryocyte growth and development factor (thrombopoietin) effects on blast cell and megakaryocyte growth in myelodysplasia. 967 19

C-mpl ligand acts primarily as a lineage-specific hematopoietic growth factor by promoting proliferation of megakaryocyte precursors and their differentiation into megakaryocytes and platelets. In addition to the ability of c-mpl ligand to support megakaryocytic development from CD34+ precursor cells, several lines of evidence also point to a stimulatory effect on hematopoietic stem cells. When recombinant thrombopoietin or pegylated megakaryocyte growth and development factor is administered to normal animals or humans, there is a dose-dependent increase in the platelet count. When administered following chemotherapy in animal models or humans, c-mpl ligands reduce the duration and sometimes the degree of thrombocytopenia. The issue of whether clinically relevant thrombocytopenia can be ameliorated has so far been more difficult to resolve. Because severe thrombocytopenia is not commonly seen with standard chemotherapy regimens, clinical studies examining c-mpl ligands for their ability to ameliorate chemotherapy-induced thrombocytopenia will focus on treatment of acute leukemias and bone marrow transplantation. The potential utility of c-mpl ligands for treatment of myelodysplastic syndromes, aplastic anemias, or in HIV infection, will have to be evaluated in the future. Possibly the greatest potential of thrombopoietic growth factors in the near future may be in transfusion medicine, to collect and to store platelets from healthy donors or in autologous settings.
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PMID:Megakaryocytic growth factors: is there a new approach for management of thrombocytopenia in patients with malignancies? 1004 50

Megakaryocytic differentiation of progenitor cells was investigated in nine patients with low-risk myelodysplastic syndromes (MDS) (eight refractor anemia [RA] and one RA with ringed sideroblasts [RARS] and five patients with high-risk MDS (two RA with excess of blasts [RAEB] and three RAEB in transformation [RAEB-T]). Bone marrow-derived CD34+ cells were enriched to a purity of 87% +/- 2% (mean +/- SEM) and assayed in short-term suspension cultures in the presence of 10 ng/mL of PEGylated recombinant human megakaryocyte (MK) growth and development factor (PEG-rHuMGDF) and in addition to 50 ng/mL stem cell factor and 10 ng/mL interleukin-3. Cells of the megakaryocytic lineage were identified by flow cytometric analysis of CD42b (GP1b) and mature MKs by morphologic criteria. Transcription of c-mpl receptor-specific mRNA in the CD34+ cells of these patients was investigated by full-length reverse transcriptase polymerase chain reaction of the p form of c-mpl as well as of the alternative splice product c-mpl k. CD34+ cells from seven healthy bone marrow donors served as controls. Differentiation along the MK pathway was stimulated in five patients with RA. C-mpl mRNA was expressed in the CD34+ cells in all cases. In three low-risk patients the capacity for in vitro MK growth was absent or minimal even though mRNA for c-mpl receptor was detected in the CD34+ cells of this group as well. In patients with high-risk MDS, PEG-rHuMGDF stimulated in vitro MK growth from CD34+ cells in only one of five cases. As in the patients with low-risk MDS, c-mpl mRNA for both c-mpl p and c-mpl k splicing products was detected. These results indicate that the in vitro response to stimulation with c-mpl ligand discriminates between two groups of patients with low-risk MDS and that the observed defect in megakaryocytic development is unrelated to the level of c-mpl expression in both low-risk and high-risk MDS.
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PMID:Characterization of defective megakaryocytic development in patients with myelodysplastic syndromes. 1008


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