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)

To evaluate the effects of colony-stimulating factors (CSFs) on pathological cells from myelodysplastic syndromes (MDS), the blast cells from 19 MDS patients (eight low-risk MDS, six high-risk MDS, and five leukemic transformation of MDS [LT-MDS]) and four normal volunteers were successfully enriched by separating CD34-positive cells by the use of immunomagnetic beads, and their responsiveness to granulocyte or granulocyte-macrophage CSF (G-CSF or GM-CSF) was examined in short-term liquid suspension culture. The proliferation of MDS blast cells was clearly promoted by these CSFs in all cases examined, but considerable percentages of them often remained immature compared with the favorable maturation of normal blast cells, especially in the more advanced disease groups (LT-MDS and high-risk MDS) that included two prominent cases with a remarkable blast cell growth without maturation induction by CSFs. The expression of esterase activities was rather sluggish in the MDS cases, in contrast to normal expression. These data showed that MDS blast cells proliferate in response to CSFs but that maturation is less than that observed with normal blast cells in vitro. Much care should be taken with in vivo application of CSFs to high-risk MDS patients.
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PMID:Altered responses of purified blast cells from the myelodysplastic syndromes to colony-stimulating factors in vitro: comparison with normal blast cells. 751 87

In a search for a mechanism to explain the impaired growth of progenitor cells in patients with myelodysplastic syndromes (MDS), marrow CD34+ cells were purified up to 94.9% +/- 4.2% for normal individuals and 88.1% +/- 17.6% for MDS patients, using monoclonal antibodies and immunomagnetic microspheres (MDS CD34+ cells). Phenotypic subpopulations of these CD34+ cells were analyzed for CD38, HLA-DR, CD33, CD13, CD14, CD41 and CD3 plus CD19, in association with proliferative and differentiative capacities. The 15 studies performed included 12 MDS patients. Coexpression rate of CD13 significantly increased in the MDS CD34+ cell population with a value of 91.4% +/- 11.6% and ranging from 60.3% to 100%, and exceeded 99% in four studies, whereas that of normal CD34+ cells was 49.9% +/- 15.8%, ranging from 28.2% to 70.1% (P < .001). Coexpression rate of CD38, HLA-DR, CD33, CD14, and CD3 plus CD19 in MDS CD34+ cells did not significantly differ from that of normal CD34+ cells. The total number of colonies and clusters grown from 100 normal marrow CD34+ cells was 40.4 +/- 8.6, the range being from 27.2 to 50.3; this varied in MDS marrow CD34+ cells with a value of 34.0 +/- 28.7, the range being 0 to 95.9. The lineage of colonies and clusters promoted by MDS marrow CD34+ cells was predominantly committed to nonerythroid with impaired differentiation in 13 of 15 studies (87%). CD13 is first expressed during hematopoiesis by colony-forming unit granulocyte-macrophage and is absent in erythroid progenitors. Therefore, this study provides direct evidence for the lineage commitment of MDS CD34+ cells to nonerythroid with impaired differentiation and explains the mechanism of nil or low colony expression of MDS progenitor cells to erythroid lineage.
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PMID:Proliferation and differentiation of myelodysplastic CD34+ cells: phenotypic subpopulations of marrow CD34+ cells. 752 67

Myelodysplastic syndromes (MDS) are clonal disorders of the multipotent hematopoietic stem cell characterized by ineffective hematopoiesis and associated with marrow hypercellularity, increased intramedullary cell death and peripheral cytopenias of varying severity. Patients with myelodysplasia have a propensity (20% to 30% of cases) to undergo transformation into acute myeloid leukemia (AML), and a large body of evidence indicates that MDS represent steps in the multiphasic evolution of AML. Progression of the disease is characterized by expansion of the abnormal clone and inhibition of normal hematopoiesis leading to deterioration of the blood cell count and/or development of AML. MDS are relatively unusual in childhood, representing only 3% of pediatric hematological malignancies, although it has been reported that up to 17% of pediatric AML cases may have a previous myelodysplastic phase. The first systematic attempt at morphological classification of MDS was provided by the French-American-British (FAB) group. However, the FAB classification of MDS is only partially applicable in children. Some variants are extremely rare or absent (refractory anemia with ring sideroblasts and chronic myelomonocytic leukemia), and other peculiar pediatric disorders, represented by juvenile chronic myelogenous leukemia (JCML) and the monosomy 7 syndrome, are not included. Moreover, since there is a partial overlap between pediatric MDS and myeloproliferative disorders and the variants occurring in young children have rather specific features, some confusion still surrounds the nosographical definition of childhood MDS, so that none of the proposed classifications are widely accepted and used. Characteristically, some genetic conditions such as Fanconi's anemia, Shwachman's and Down's syndromes predispose to the development of MDS in childhood. The most common variants of childhood MDS are represented by JCML and the monosomy 7 syndrome, both disorders typically occurring in young children. JCML is characterized by a spontaneous growth of granulocyte-macrophage progenitors that show a striking hypersensitivity to granulocyte-macrophage colony-stimulating factor. Clinical presentation resembles that of some myeloproliferative disorders, with massive organomegaly usually not observed in the classically reported variants of MDS. Clinical features of the monosomy 7 syndrome resemble those observed in JCML and a differential diagnosis between these two entities relies upon the higher percentage of fetal hemoglobin, the more pronounced decrease in platelet count and, in some cases, the lack of the peculiar cytogenetic abnormality in the latter. With the number of children being cured of cancer constantly rising, a significant increase in secondary or chemotherapy-related myelodysplasia is being observed, and these disorders represent a formidable challenge for pediatric hematologists due to their poor response to chemotherapy.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Myelodysplastic syndromes: the pediatric point of view. 767 22

Steel factor (SLF, c-kit ligand), a potent costimulating cytokine in vitro for myeloid progenitor cells from normal donors, is currently being evaluated in clinical trials for effects on hematopoiesis. Based on a preliminary observation that colony-stimulating factor (CSF)-responsive myeloid progenitor cells (CFU-GM) from a few patients with acute myeloid leukemia (AML) did not respond to the costimulating effects of SLF, we evaluated responsiveness of bone marrow or blood CFU-GM from 26 patients with either AML, chronic myeloid leukemia (CML) or myelodysplastic syndrome (MDS) to the effects in vitro of SLF and/or granulocyte-macrophage CSF (GM-CSF). Cells from all 26 patients responded to the stimulating effects of GM-CSF, but marked heterogeneity was detected in each disease category to the costimulating effects of SLF. Nine of 13 patients with AML, 2 of 6 patients with CML and 4 of 7 patients with MDS had clonogenic cells that did not respond significantly to the costimulating effects of SLF. In a more limited study of cells from patients with MDS, it was noted that if the CFU-GM of that patient did not respond to SLF enhancement of CSF-induced colony formation, neither did the erythropoietin (Epo)-dependent erythroid (BFU-E) or multipotential (CFU-GEMM) cells of that patient (3 cases of refractory anemia [RA] evaluating bone marrow and in 1 case blood progenitors as well). If CFU-GM responded, BFU-E and CFU-GEMM responded (bone marrow from 1 patient with chronic myelomonocytic leukemia [CMMol]). Clinical criteria did not readily distinguish between patients who had SLF-responsive vs. -nonresponsive clonogenic cells. While the mechanistic reason for this heterogeneity in responsiveness is not clear, these differences should be carefully considered for possible clinical trials with SLF in patients with acute and chronic myeloid leukemia and MDS.
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PMID:Differential responses of myeloid progenitor cells from patients with myeloid leukemia and myelodysplasia to the costimulating effects of steel factor in vitro. 768 84

The colony-stimulating factors (CSFs) have emerged as effective drugs in a variety of clinical situations. These drugs stimulate the production and activity of haematopoietic cells in vitro and in vivo. Two members of this group, granulocyte CSF (G-CSF) and granulocyte-macrophage CSF (GM-CSF), have been approved in the US and Europe for use following cytotoxic chemotherapy and autologous bone marrow transplantation. Other uses of the CSFs include myelodysplastic syndromes, aplastic anaemia, the acquired immunodeficiency syndrome (AIDS) and cyclic and congenital neutropenias. Although CSFs have generally been well tolerated in clinical use there are a number of theoretical concerns, including disease acceleration, biased stem cell commitment and bone marrow exhaustion. New CSFs are currently under development. Combinations of growth factors in the future may maximise effectiveness while minimising toxicity.
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PMID:Use and toxicity of the colony-stimulating factors. 768 34

In the current study, we used a monoclonal antibody-based enzyme-linked immunosorbent assay and bioassay to assess leukemia inhibitory factor (LIF) protein levels, activity, and function in supernatants of 59 adherent layers derived from acute and chronic myelogenous leukemia, myelodysplastic syndrome, and hairy cell leukemia patients and from normal controls. We demonstrate that biologically active LIF protein is constitutively produced and secreted by cultured bone marrow stromal cells from all of the studied subjects. Furthermore, various cytokines can alter endogenous LIF protein levels. Twenty-four h of exposure to recombinant human (rh) interleukin (IL) 4 (100 units/ml) significantly decreased LIF protein levels in adherent layer conditioned media [median base line level, 2.6 ng/ml; range, 1.6-8.0 ng/ml; median post rhIL-4 exposure levels, 1.9 ng/ml; range, 0.9-5.8 ng/ml (n = 7; P = 0.022)]. In contrast, rhIL-1 beta and rh tumor necrosis factor alpha consistently increased LIF protein levels. In the samples exposed to 50 units/ml rhIL-1 beta, median base line LIF level was 2.6 ng/ml; median post-LIF level was 9.0 ng/ml (n = 8; P = 0.014). In the two samples exposed to rh tumor necrosis factor alpha (200 units/ml), LIF levels increased from baseline levels of 2.6 and 2.7 ng/ml to postexposure levels of 7.7 and 12.2 ng/ml, respectively. Finally, the presence of LIF may be relevant to both normal and malignant hematopoietic processes as evidenced by: (a) LIF protein levels in adherent layer conditioned media were significantly elevated in samples from patients with a spectrum of hematological neoplasms [acute myelogenous leukemia: median level, 3.0 ng/ml (range, 1.6-11.0 ng/ml); myelodysplastic syndrome: median level, 4.5 ng/ml (range 1.4-15.5 ng/ml); hairy cell leukemia; median level, 3.5 ng/ml (range 2.2-10.3 ng/ml); chronic myelogenous leukemia-chronic phase: median level, 4.35 ng/ml (range 0.3-19.0 ng/ml); and chronic myelogenous leukemia-blast crisis: median level, 6.25 ng/ml (range 0.7-20.3 ng/ml)] as compared to samples from normal individuals (median level, 2.0 ng/ml; range, 0.7-4.6 ng/ml; P < 0.05); and (b) in normal controls, in vitro abrogation of endogenous LIF bioactivity by neutralizing antibody decreased the number of committed granulocyte-macrophage hemopoietic progenitors.
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PMID:Leukemia inhibitory factor in long-term adherent layer cultures: increased levels of bioactive protein in leukemia and modulation by IL-4, IL-1 beta, and TNF-alpha. 813 98

Patients successfully treated for a malignancy with cytotoxic therapy have an increased risk of developing secondary myelodysplasia (MDS) and acute myeloid leukemia (AML). We report a patient in remission from Hodgkin's disease (HD) who remains hematologically normal 4 years after combination chemotherapy, but who has biological and genetic abnormalities characteristic of myelodysplasia. X-inactivation analysis using a 5' phosphoglycerate kinase (PGK) probe demonstrates polyclonal hematopoiesis, but cytogenetic analysis reveals a clonal population with a minority of metaphases having a 7q-deletion. NRAS mutations are not detectable 1 year after treatment, but are present in two separate clones (at codons 12 and 15) analyzed by single-stranded conformational polymorphism (SSCP), followed by cloning and sequencing 4 years after treatment. The presence of an activated NRAS with the same codon 12 mutation was independently confirmed by the nude mouse tumorigenicity assay. In vitro peripheral blood granulocyte-macrophage colony-forming units (CFU-GM) have changed from normal to undetectable levels while erythroid burst forming units (BFU-E) were significantly reduced on two occasions during the period of observation. These abnormalities are characteristic of MDS. Continued clinical follow-up will determine whether these evolving genetic and biological abnormalities pre-date the onset of clinical and morphological features of MDS.
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PMID:Non-dysplastic myelodysplasia? 815 65

Ten patients with myelodysplastic syndromes were investigated using in vitro colony assay of bone marrow cells and chromosome analysis of single colonies. The result was compared with conventional cytogenetic analysis of bone marrow cells. The chromosome abnormalities included were 5q-, +8, -7, 11q-, -Y and one complex karyotype. Erythroid colony formation was reduced in eight patients, while the number of granulocyte-macrophage colony-forming units was normal or increased. Cytogenetic examination of single colonies showed that both chromosomally normal and abnormal stem cells had colony forming ability. The proportion of cytogenetically abnormal colonies varied between 25 and 100% of analysed colonies. No further clones than those found in direct cytogenetic analysis were revealed after in vitro growth. One patient with a 5q- abnormality and one patient with a -7 abnormality showed a significantly lower proportion of cytogenetically abnormal colonies than the proportion of abnormal cells in the direct bone marrow chromosome preparation. One patient with a +8 abnormality showed a growth advantage of the +8 clone in comparison with the chromosomally normal clones, but this was not statistically significant. In two patients a chromosomally changed stem cell gave rise to both erythroid and myeloid colonies. The FAB-class did not seem to influence the growth of either chromosomally normal or abnormal colonies.
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PMID:Variable growth in vitro of chromosomally different stem cells in myelodysplastic syndromes. 823 Dec 33

Recombinant cytokines are now available for clinical use. Several colony-stimulating factors (CFS) have been identified which induce activation, proliferation and maturation of myeloid lineage cells. Recent therapeutic trials with granulocyte-macrophage colony-stimulating factors (GM-CSF) in association with chemotherapy, bone marrow transplantation and leukemia treatment are reviewed. GM-CSF as primary treatment for myelodysplasia and other types of bone marrow failure is also of interest. Colony-stimulating factor therapy in AIDS may be useful in order to reduce myelodepression caused by antiviral treatment and chemotherapy for associated malignancies like Kaposi's sarcoma. However, the effect of neutrophil count increase on infection is far from clear, and the real benefit of GM-CSF in cancer therapy has yet to be demonstrated.
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PMID:Therapeutic use of granulocyte-macrophage colony-stimulating factor (GM-CSF). A review of recent experience. 836 27

A 30-year-old Chinese man with acquired amegakaryocytic thrombocytopenic purpura (AATP) and a Ph chromosome is reported. At presentation, he had severe thrombocytopenia resulting in epistaxis, gingival bleeding, and ecchymoses, while other hematologic values were within the normal range. Bone marrow aspiration showed no megakaryocytes, with a normal appearance of erythroblastic and granulopoietic series. He failed to respond to prednisone treatment, and underwent a progress from isolated thrombocytopenia to full pancytopenia. At last he died of spontaneous intracranial hemorrhage. An in vitro culture for granulocyte-macrophage precursors showed very few colonies. Karyotypic analysis revealed a standard Ph chromosome translocation, t(9;22)(q34;q11), in the majority of bone marrow cells. Southern blot analysis using a 3' bcr-HE probe didn't detect a rearrangement within the bcr DNA sequence. This patient, in fact, was a myelodysplastic disorder, initially presenting as AATP. The diagnosis of chronic myelogenous leukemia was excluded on the basis of clinical and hematologic findings. The heterogeneity of Ph chromosome in myelodysplastic syndrome is discussed.
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PMID:Acquired amegakaryocytic thrombocytopenic purpura with a Philadelphia chromosome. 837 1


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