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 SV40 large T gene under the control of immunoglobulin enhancer induced hyperproliferation of multilineage hematopoiesis in transgenic mice. Huge splenomegaly was the major gross abnormality; mice were rather anemic, and neither leukoerythroblastosis nor invasion into tissues such as liver, kidneys or lymph nodes was common. In the latter phases of the disease, the proliferating cell type tended to shift to a variety of single-lineage hematopoiesis, but the majority of mice still showed the presence of multilineage hematopoiesis; such cells were somewhat dysplastic but low in neoplastic potential. A long-term observation by transplantation of the hematopoietic cells into lethally irradiated C57BL/6 mice resulted in a variety of neoplastic growths in the recipients; not only was myelodysplastic hypercellularity seen, but also single-lineage hematopoietic malignancies such as B cell lymphomas/leukemias, histiocytic malignancies and even myeloid leukemias. The disease bore the proliferative feature solely in the spleen and bone marrow, and the transition from multilineage myelodysplasia into single-lineage hematopoiesis at some frequency is reminiscent of myelodysplastic syndromes (MDS) in humans. The results that the SV40 large T antigen was expressed in every proliferating cell, and that there was no apparent increase in any colony-stimulating cytokine(s), together with the results of the transplantation assays, suggested that the hyperproliferation of the hematopoietic cells was a direct consequence of the expression of SV40 large T antigen in these cells themselves.
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PMID:MDS-like experimental myelodysplasia: multilineage abnormal hematopoiesis in transgenic mice harboring the SV40 large T antigen under an immunoglobulin enhancer. 850 May 78

The mRNA expression of alkaline phosphatase (ALP), myeloperoxidase (MPO), defensin and G-CSF receptor (G-CSFR) in bone marrow cells of normal individuals and myeloid disorders, with or without in vitro stimulation by myeloid cell growth factors, i.e. G-CSF, GM-CSF and IL-3, were examined as markers for myeloid cell differentiation in both mononuclear cell (MNC) and polymorphonuclear cell (PMN) fractions. Without any stimulation, ALP mRNA was expressed only in PMNs, G-CSFR mRNA in PMNs were expressed stronger than in MNCs; both MPO and defensin mRNA were expressed to the same degree in both fractions. With stimulation, the ALP mRNA expression in both fractions was strongly enhanced by G-CSF, but the expression was inhibited by GM-CSF and/or IL-3. MPO mRNA expression was stimulated by G-CSF and/or GM-CSF in MNCs. G-CSFR mRNA expression was enhanced by G-CSF in both fractions. Defensin mRNA expression was inhibited by G-CSF. In cases of myelodysplastic syndrome and chronic myelogenous leukaemia which display a suppressed maturation of myeloid cells, our results demonstrated an almost normal response to these growth factors. Our results suggest that studies on these myeloid marker mRNA expressions would provide more knowledge about the differentiation state and cytokine reactivity of myeloid cells in normal individuals as well as various disorders.
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PMID:Effects of myeloid cell growth factors on alkaline phosphatase, myeloperoxidase, defensin and granulocyte colony-stimulating factor receptor mRNA expression in haemopoietic cells of normal individuals and myeloid disorders. 856 17

A previously healthy 74-year-old patient without a prior history of hematological disease presented with an acute respiratory infection. Peripheral pancytopenia led us to perform a bone marrow biopsy, and the diagnosis of undifferentiated acute myelogenous leukemia (AML, 61% blasts) was made. Following antibiotic treatment and resolution of the infection, the blast count in the bone marrow fell to 2%, leaving a clinicopathologic picture consistent with myelodysplastic syndrome (MDS, French-American-British type refractory anemia), and the patient survived for a total of 16.5 months following the initial presentation with cytokine support. A preterminal blast proliferation occurred during a bacterial ear infection and rapidly responded to a withdrawal of cytokine support, antibiotic therapy, and hydroxyurea. The patient succumbed ultimately to an apparent myocardial infarct. Clinicians should consider transient acceleration of MDS in their differential diagnosis when confronted with apparent AML and acute infection.
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PMID:Recent-onset myelodysplastic syndrome mimicking acute leukemia during infection. 859 13

The effect of an ex vivo expansion culture system using multiple cytokine combinations was evaluated in 38 cases of myelodysplastic syndrome (MDS) with the aim of overcoming the defective in vitro growth of haemopoietic progenitor cells. A combination of four growth factors (GF) including SCF, IL-3, IL-6 and GM-CSF was identified as the optimal combination for expanding clonogenic progenitor cells in MDS bone marrow liquid cultures. The cultures of 50% of the patients (19/38) responded to GF stimulation (mean CFU-GM fold increase 15.65+/-48 at week 4) and showed morphological features of normal and/or dysplastic myeloid differentiation. In 12/38 cases (31%), complete unresponsiveness to multiple cytokine stimulation was observed; a small number of patients (7/38) showed progressive leukaemic growth along the cultures with the presence of 100% immature blasts at week 4. GM-CSF and c-kit receptors, analysed by immuno-histochemistry in 10 patients, were over-expressed in responding patients and either lacking or down-regulated in non-responders. Fluorescence in situ hybridization (FISH) analysis of cultured interphase cells of nine patients (trisomy 8 in eight patients) showed a clear-cut increase in the percentage of cells with three signals in the two responding patients, thus indicating the expansion of a MDS clone. Multiple cytokine liquid cultures seem to be able to override the refractoriness of MDS progenitor cells to GF stimulation in many cases, revealing a heterogeneity which may have prognostic implications and should be considered in ex-vivo and in vivo clinical trials with cytokine combinations.
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PMID:Response of myelodysplastic syndrome marrow progenitor cells to stimualtion with cytokine combinations in a stroma-free long-term culture system. 861 15

A cytogenetically normal man with severe aplastic anemia was treated with granulocyte colonystimulating factor (G-CSF), erythropoietin (EPO), cyclosporin A, anti-thymocyte globulin, and interleukin-6 (IL-6), which resulted in a gradual improvement in his neutrophil count and hemoglobin level. After 2 years of the therapy, monosomy 7 was detected during cytogenetic analysis of his bone marrow, which evolved during a period of 5 months into acute myeloblastic leukemia. An in vitro proliferation assay of cytokine responses showed that leukemic blasts were sensitive only to G-CSF, and not to EPO or IL-6. Although allogeneic bone marrow transplantation from an HLA-matched unrelated donor was carried out in the non-remission stage, the patient died of systemic fungal infection on day 25, without any evidence of hematological engraftment. As long-term use of cytokines and immunomo-suppressants in patients with severe aplastic anemia may induce or hasten the onset of a malignant transformation, careful attention must be paid to clonal evolution. Due to the poor prognosis of secondary myelodysplasia and leukemia, allogeneic bone marrow transplantation for such patients must be carried out early in the course of the disease.
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PMID:Transformation of severe aplastic anemia into acute myeloblastic leukemia with monosomy 7. 864 49

To evaluate the clinical usefulness of IL-2 in myelodysplastic syndromes (MDS) the in vitro effects of interleukin-2 (IL-2) on blast cell proliferation, clonogenic activity, cytokine release and cell mediated cytotoxicity were examined in 49 MDS patients. Morphological analyses of bone marrow (BM) cytospin preparations showed a significant decrease in the number of blast cells in MDS after incubation with IL-2. Incubation of bone marrow mononuclear cells (BMMNCs) with IL-2 induced a significant increase in the number of CFU-GM in comparison with untreated controls. gamma-IFN and GM-CSF, but not alpha-TNF were found to be released in significant amounts by the BMMNCs cultured with IL-2. No significant differences in the surface phenotypes of fresh lymphocytes were observed between the normal and MDS subjects. After incubation with IL-2, we observed a significant increase in the number of CD3-/CD56+ cells in both normal and MDS subjects. Peripheral blood (PB) and BM NK activity against K562 was significantly greater in MDS after stimulation with IL-2. These data suggest the clinical usefulness of IL-2 in a large subgroup of patients as it may reduce the percentage of blasts and increase clonogenic capacity and cell-mediated cytotoxicity.
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PMID:In vitro effects of IL-2 on NK-activity, clonogenic potential, blast cell proliferation and cytokine release of MDS bone marrow patients. 868

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

A poorly defined transforming event(s) affects the pluripotential bone marrow (BM) stem cell in myelodysplastic syndromes (MDS), conferring a growth advantage upon it which leads eventually to monoclonal hematopoiesis. The progeny of this transformed ancestor undergo recognizable albeit dysplastic maturation. We propose that this picture is further complicated by a variety of cytokines, tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta) and interleukin 1beta (IL-1beta) which exert a dual effect on the diseased cells. The immature CD34+ cells are stimulated to proliferate, while their later differentiated daughters are induced to undergo apoptosis accounting for the clinical syndrome of pancytopenia despite hypercellular BMs. Studies directed at measuring the rates of proliferation and apoptosis as well as the levels of TNF-alpha, TGF-beta and IL-1beta confirm this hypothesis and are presented in greater detail. A novel approach towards MDS therapy emerges as a result of this paradigm shift based upon the premise that anti-cytokine therapy would prevent excessive intramedullary apoptosis and result in improved cytopenias as well as cause a slowing down of the diseased precursor cell proliferation resulting in resumption of polyclonal hematopoiesis. Because a number of cytokines function through common lipid second messengers, interruption of this pathway should theoretically cause disruption in the signalling of a cascade of cytokines.
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PMID:A paradigm shift in myelodysplastic syndromes. 884

We report a therapy-related MDS (RAEB) patient with eosinophilia, unbalanced translocation der(7)t(1;7) (q12;q22) and lung cancer. We observed no increase in cytokine levels in serum or in the conditioned medium (CM) of peripheral T cells cultured with or without IL-2. When bone marrow (BM) cells were cultured with GM-CSF, IL-3 and SCF in a semisolid system, the colonies were exclusively eosinophilic. Cytogenetic analysis of the colony cells identified the same chromosome abnormality in all metaphases to that of BM cells. Suspension and clonogenic colony assay of BM cells cultured with various cytokines showed predominant eosinophilic growth and differentiation with GM-CSF, but not with the other cytokines examined. These findings, together with mild morphological abnormalities of eosinophils, indicate clonal involvement of eosinophils in the myelodysplastic syndrome (MDS) clone, and that the eosinophilia was derived from the neoplastic clone with the translocation and was not associated with the patient's lung cancer.
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PMID:Clonal involvement of eosinophils in therapy-related myelodysplastic syndrome with eosinophilia, translocation t(1;7) and lung cancer. 898 50

Interleukin-3 (IL-3) is a pleiotropic cytokine which has stimulatory effects on a broad range of hematopoietic progenitor cells. These effects have led to the use of IL-3 in clinical trials for the treatment of aplastic anemia and myelodysplastic syndrome as well as to stimulate bone marrow recovery in patients who have received high-dose therapy and bone marrow/stem cell transplantation. However, because one study suggested that IL-3 may also stimulate the growth of follicular small cleaved cell lymphoma (FSCCL) cells in vitro, it was concerning that the use of IL-3 after bone marrow transplantation in patients with FSCCL may stimulate the growth of undetectable minimal residual tumor cells resulting in early relapsed disease. In contrast to these observations, our own in vitro studies demonstrated that IL-3 inhibited FSCCL cells in short-term culture in a dose-dependent manner. Subsequently, we conducted a phase II clinical trial using single agent IL-3 for the treatment of patients with follicular low grade lymphoma. Our clinical data did not support the hypothesis that IL-3 is a growth stimulator of FSCCL.
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PMID:In vitro and in vivo biologic effects of interleukin-3 (IL-3) in follicular low-grade lymphoma. 925 Jul 83


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