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)

Deletions of the long arm of chromosome 20 are associated with several myeloid malignancies and, in particular, with myeloproliferative disorders and myelodysplastic syndromes (MDS). Together with deletions of chromosome 5q and chromosome 7q, chromosome 20q deletions have previously been thought to be restricted to myeloid cells in patients with MDS. We report here that deletion of chromosome 20q in MDS can arise in a multipotent precursor of both myeloid cells and B cells. Clonal Epstein-Barr virus (EBV)-transformed cell lines, both with and without a 20q deletion, have been isolated from a patient with MDS. Moreover, these cell lines have been shown to provide a useful physical mapping tool and have been used to confirm the interstitial nature of the 20q deletion. Microsatellite polymerase chain reaction (PCR) and PCR analysis of PGK gene methylation have been used to study highly purified populations of peripheral blood cells. The 20q deletion was detectable by microsatellite PCR in peripheral blood granulocytes and monocytes but not in B cells or T cells. Clonality of the different lineages followed the same pattern as the 20q deletion. This represents the first report in which a chromosome abnormality associated with MDS has been immortalized in an EBV-transformed lymphoblastoid cell line. Furthermore, our data show that patients with apparent myeloid restriction of a chromosome deletion may in fact have a disease arising in a multipotent cell with both myeloid and lymphoid potential.
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PMID:Deletion of chromosome 20q in myelodysplasia can occur in a multipotent precursor of both myeloid cells and B cells. 818 Mar 77

Because human lymphotoxin (LT) was originally isolated from a lymphoblastoid cell line, we investigated the role of this molecule in three newly established Epstein-Barr virus (EBV)-infected human B cell lines. These lines were derived from acute lymphoblastic leukemia (Z-6), myelodysplastic syndrome (Z-43), and acute myelogenous leukemia (Z-55) patients who had a prior EBV infection. Each lymphoblastoid cell line had a karyotype that was different from that of the original parent leukemic cells, and all expressed B cell, but not T cell or myeloid surface markers. In all three lines, rearranged immunoglobulin heavy chain joining region (JH) bands were found, and the presence of EBV DNA was confirmed by Southern blotting. Z-6, Z-43, and Z-55 cell lines constitutively produced 192, 48, and 78 U/ml LT, respectively, as assessed by a cytotoxicity assay and antibody neutralization. Levels of tumor necrosis factor (TNF) were undetectable. Scatchard analysis revealed that all the cell lines expressed high-affinity TNF/LT receptors with receptor densities of 4197, 1258, and 1209 sites/cell on Z-6, Z-43, and Z-55, respectively. Furthermore, labeled TNF binding could be reversed by both unlabeled TNF, as well as by LT. Studies with p60 and p80 receptor-specific antibodies revealed that the three lines expressed primarily the p80 form of the TNF receptor. When studied in a clonogenic assay, exogenous LT stimulated proliferation of all three cell lines in a dose-dependent fashion at concentrations ranging from 25 to 500 U/ml. Similar results were obtained with [3H]TdR incorporation. Monoclonal anti-LT neutralizing antibodies at concentrations of 25-500 U/ml inhibited cellular multiplication in a dose-dependent manner. It is interesting that in spite of a common receptor, TNF (1,000 U/ml) had no direct effect on Z-55 cell growth, whereas it partially reversed the stimulatory effect of exogenous LT. In addition, TNF inhibited Z-6 and Z-43 cell proliferation, and its suppressive effect was reversed by exogenous LT. Both p80 and p60 forms of soluble TNF receptors suppressed the lymphoblastoid cell line proliferation and their inhibitory effect was partially reversed by LT. Our data suggest that (a) LT is an autocrine growth factor for EBV-transformed lymphoblastoid B cell lines; and (b) anti-LT antibodies, soluble TNF/LT receptors, and TNF itself can suppress the growth of lymphoblastoid cells, probably by modulating or competing with LT.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Lymphotoxin is an autocrine growth factor for Epstein-Barr virus-infected B cell lines. 838 56

In the 8;21 translocation, the AML1 gene, located at chromosome band 21q22, is translocated to chromosome 8 (q22), where it is fused to the ETO gene and transcribed as a chimeric gene. AML1 is the human homolog of the recently cloned mouse gene pebp2 alpha B, homologous to the DNA binding alpha subunit of the polyoma enhancer factor pebp2. AML1 is also involved in a translocation with chromosome 3 that is seen in patients with therapy-related acute myeloid leukemia and myelodysplastic syndrome and in chronic myelogenous leukemia in blast crisis. We have isolated a fusion cDNA clone from a t(3;21) library derived from a patient with therapy-related myelodysplastic syndrome; this clone contains sequences from AML1 and from EAP, which we have now localized to band 3q26. EAP has previously been characterized as a highly expressed small nuclear protein of 128 residues (EBER 1) associated with Epstein-Barr virus small RNA. The fusion clone contains the DNA binding 5' part of AML1 that is fused to ETO in the t(8;21) and, in addition, at least one other exon. The translocation replaces the last nine codons of AML1 with the last 96 codons of EAP. The fusion does not maintain the correct reading frame of EAP and may not lead to a functional chimeric protein.
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PMID:The 3;21 translocation in myelodysplasia results in a fusion transcript between the AML1 gene and the gene for EAP, a highly conserved protein associated with the Epstein-Barr virus small RNA EBER 1. 839 54

Myelodysplastic syndrome (MDS) in childhood is considered to be very rare and detailed pathobiological data are scarce. More biological information regarding MDS in children is clearly needed and in vitro culture studies provide one possibility for gaining further pathophysiological insights into this malignancy. Here, we incubated bone marrow samples from 30 children with MDS in liquid suspension culture in order to grow the transformed cells in vitro. In most cultures, the hematopoietic cells died quickly and only fibroblastic (stromal) background layers proliferated temporarily; several normal Epstein-Barr virus (EBV)-transformed B-lymphoblastoid cell lines (B-LCL) were established. Only in one instance, albeit from the peripheral blood and not from the bone marrow, could we establish a cell line, termed MUTZ-1, from the malignant cells of a 5-year-old girl with MDS (FAB subtype refractory anemia with excess of blasts). The MDS arose from a pre-existing Fanconi anemia and progressed quickly to an acute myeloid leukemia (FAB M2). Despite positivity for EBV, MUTZ-1 is not an EBV + B-LCL and further characterization of MUTZ-1 confirmed the derivation from the transformed clonal cells. Immunophenotyping showed a pre B-cell surface marker profile (CD10+ CD19+ cytoplasmic IgM+); receptor gene rearrangement analyses underlined the clonal B-cell nature of MUTZ-1 cells. MUTZ-1 cells exhibit a highly rearranged, unstable karyotype with a high frequency of spontaneous chromatid breaks and exchanges; del(5q) and additional rearrangements involving chromosome 5 [der(15)t(5;15)] were detected. The present data and results from a few other MDS-derived cell lines suggest that the transforming event in MDS seems to occur in an immature pluripotent progenitor cell. The new MDS-derived continuous cell line MUTZ-1 provides a useful in vitro model system for studies on the pathogenetic events leading to MDS.
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PMID:In vitro culture studies of childhood myelodysplastic syndrome: establishment of the cell line MUTZ-1. 916 45

The first case of B-cell lymphoma of brain in a patient with myelodysplastic syndrome (MDS) was reported. A 68-year-old man was admitted because of anemia, fever, and thrombocytopenia and was diagnosed as having MDS (refractory anemia with excess of blasts) on the basis of the findings of bone marrow aspiration and chromosomal analysis. The patient was followed up without chemotherapy, but a brain tumor appeared after 3 years. Histologic and immunohistologic examinations revealed diffuse large B-cell lymphoma. Mutations of the c-kit proto-oncogene (stem cell factor receptor) and the p53 tumor-suppressor gene were examined in the MDS lesion and malignant lymphoma (ML) by the polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP) method followed by direct sequencing. The p53 mutation was not found in either MDS or ML, but a nonsense mutation (Try-557 --> stop) in exon 11 of the c-kit, which might lead to dysfunction of tyrosine kinase activity, was detected in MDS. This is the first report of c-kit mutation in MDS. Epstein-Barr virus (EBV) genome was demonstrated in the nucleus of brain ML cells by in situ hybridization with EBV-encoded RNA-1 probe. Immunohistochemistry showed that the tumor cells expressed latent infection gene products, including EBV nuclear antigen-2 and latent membrane protein-1. This pattern of latent gene expression was Lat III, which is usually found in malignant lymphomas developing in immunocompromised hosts. These findings suggest that a profound pancytopenia in MDS resulted in an immunodeficient condition, after which EBV-positive B-cell lymphoma of brain developed.
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PMID:Epstein-Barr virus associated B-cell lymphoma of brain developing in myelodysplastic syndrome with c-kit mutation (Try-557 -->stop). 1107 41

Leukocyte adhesion deficiency type I (LAD-1) is a disorder associated with severe and recurrent bacterial infections, impaired extravascular targeting and accumulation of myeloid leukocytes, altered wound healing, and significant morbidity that is caused by absent or greatly diminished surface expression of integrins of the beta2 class. We report clinical features and analysis of functions of cells from a patient with a myelodysplastic syndrome and infectious complications similar to those in the severe form of LAD-1, but whose circulating neutrophils displayed normal levels of beta2 integrins. Analysis of adhesion of these cells to immobilized ligands and to endothelial cells and assays of cell-cell aggregation and chemotaxis demonstrated a profound defect in adhesion mediated by beta2 integrins indicative of a variant form of LAD-1. A novel cell line established from Epstein-Barr virus-transformed lymphoblasts from the subject demonstrated deficient beta2 integrin-dependent adhesive function similar to that of the primary leukocytes. In addition, these cells had markedly impaired beta1 integrin-dependent adhesion. Sequence analysis and electrophoretic mobility of beta1 and beta2 proteins from the cell line demonstrated that the defects were not a result of structural abnormalities in the integrin subunit chains themselves and suggest that the adhesive phenotype of these cells is due to one or more abnormalities of inside-out signaling mechanisms that regulate the activity of integrins of these classes. These features define a unique LAD-1 variant syndrome that may reveal important insights that are generally relevant to inside-out signaling of integrins, a molecular process that is as yet incompletely understood.
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PMID:A novel syndrome of variant leukocyte adhesion deficiency involving defects in adhesion mediated by beta1 and beta2 integrins. 1115 96

The bone marrow (BM) in myelodysplastic syndromes (MDS) undergoes pathobiological changes that mimic an inflammatory process, and hence, an infectious etiology was suspected in these disorders. In the present report, we examined the bone marrow mononuclear cells (BMMNC) of 19 MDS patients and seven normal donors for the expression of one latency-related (Latency membrane protein 1 (LMP-1) and immediate early protein (IEP)) and one activation-related (BZLF and DNA-Pol) m-RNA each for two herpes viruses, Epstein-Barr virus (EBV) and cytomegalovirus (CMV), respectively. Reverse transcriptase polymerase chain reaction was used for this purpose. The latency-related transcripts (EBV-LMP-1 and CMV-IEP) were present in all the MDS and normal specimens. Intriguingly, 10/19 MDS specimens ( approximately 53%) and 2/7 normal donors ( approximately 28%) were positive for active EBV-BZLF (P=0.0067), while 2/19 MDS specimens ( approximately 11%) with 1/7 normal ( approximately 14%) showed active CMV-DNA-Pol (P=0.1588). Later, from another set of MDS patients (n=7) and normal donors (n=4), BM stromal cultures were established, which, at a 75% confluency, were overlaid with cord blood mononuclear cells (CBMNC). IEP was detectable in the CBMNC before and after co-incubation with MDS, as well as normal stroma. So, it was also present both in MDS and normal stromal cells. The other three were absent both in MDS and normal stromal layers. In CBMNC though, active EBV-BZLF and CMV-DNA-Pol m-RNA were detectable in one of seven MDS co-cultures each, albeit from different patients. None of the normal co-cultures showed active virus, either in stroma or CBMNC. Thus, the present report demonstrates, for the first time, the presence of active herpes viruses in the BMMNC of MDS patients and reveals the ability of the MDS stroma to support the viral activation.
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PMID:Presence of activation-related m-RNA for EBV and CMV in the bone marrow of patients with myelodysplastic syndromes. 1117 35

Two cases of cytomegalovirus (CMV) retinitis following bone marrow transplantation (BMT) from unrelated donors are reported. 1 patient had been treated for severe aplastic anemia (SAA) and the other for hypoplastic myelodysplastic syndrome (MDS). Because first line therapy with antithymocyte globulin (ATG) and cyclosporin A (CsA) had failed, BMT was performed following a conditioning regimen of ATG, cyclophosphamide, and total lymphoid irradiation. Treatment for CMV retinitis was successfully carried out with gancyclovir (systemic and intraocular injection), foscarnet, and photocoagulation (Case 1) and gancyclovir and foscarnet (Case 2). Both patients also developed Epstein-Barr virus-associated lymphoproliferative disease (EBV-LPD). We compared these 2 cases with 14 SAA patients who did not develop CMV retinitis after BMT using marrow from either HLA-identical siblings (n = 9) or from unrelated donors (n = 5). Unlike the retinitis patients, the latter 5 patients received ATG only once. The retinitis patients had significantly lower CD4+ T-cell levels in their peripheral blood than the 14 patients who did not develop CMV retinitis. We believe that repeated treatment with ATG and transplantation from unrelated donors may lead to immune dysfunction that could increase the likelihood of CMV retinitis, as well as LPD. For such BMT patients, regular ophthalmic examinations and careful testing for CMV antigenemia are recommended.
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PMID:Risk factors for cytomegalovirus retinitis following bone marrow transplantation from unrelated donors in patients with severe aplastic anemia or myelodysplasia. 1179 4

We report a patient with myelodysplastic syndrome who underwent an allogeneic bone marrow transplantation during the first remission. On day 110 he had a low-grade fever and pulmonary nodules, without superficial lymphadenopathy, were observed. The pulmonary nodules gradually increased in size and in number despite administration of anti-fungal and anti-tuberculosis agents. Transbronchial lung biopsy was performed on day 204, yielding a diagnosis of polyclonal post-transplant lymphoproliferative disease (PTLD) positive for Epstein-Barr virus (EBV)-encoded RNA (EBER) and CD20. Subsequent measurement of herpesvirus viral load demonstrated a consistent elevation of EBV viral load from day 96 to day 221. After treatment with anti-CD20 monoclonal antibody (rituximab), regression of pulmonary nodules was confirmed and the number of EBV genome copies decreased to a normal range. This case suggests that monitoring the quantitative EBV viral load may be necessary in cases of EBV-associated PTLD, even in cases presenting pulmonary nodules. Solitary pulmonary nodules may be a rare symptom of PTLD, but in such cases, an aggressive approach may be necessary to obtain a correct diagnosis.
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PMID:Multiple pulmonary nodules caused by B-cell post-transplant lymphoproliferative disorder after bone marrow transplantation: monitoring Epstein-Barr virus viral load. 1452 62

The P2X7 nucleotide receptor is an adenosine 5'-triphosphate (ATP) -gated ion channel, which is widely expressed in cells of hematopoietic origin and functions as a non-selective cation channel permeable to Na+, Ca2+, etc upon stimulation. Here, we investigated P2X7 expression in 11 human hematopoietic cell lines, representing different lineages, as well as bone marrow mononuclear cells (BMMC) samples from 87 leukemia and 10 myelodysplastic syndrome (MDS) patients. Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and flow cytometry results showed that both P2X7 mRNA and protein were detected in eight cell lines with a non-lineage-specific manner. Samples from 69 leukemia and 9 MDS patients were P2X7 positive at mRNA level. Moreover, both positive rates and relative expression levels were significantly higher in acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and MDS groups than that in normal donor group. The expression levels varied among AML subtypes with higher levels being observed in M4, M5, and M6 groups but not in M1 or M2 group. Furthermore, after one course of standard induction therapies, the remission rate in high P2X7 expression group was lower than that in either P2X7 negative group or low P2X7 expression group. Cytoplasmic free calcium increase was detected in five of eight P2X7+ cell lines as well as P2X7+ normal donor and patient samples tested, but not in three Epstein-Barr virus (EBV) positive cell lines (J6-1, Namalwa, and LCL-H) in Locke's solution upon stimulation by extracellular ATP or the more potent and specific agonist, 2',3'-O-(4-benzoyl)benzoyl-ATP (BzATP). The possible mechanisms causing the loss of P2X7 function were discussed.
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PMID:Expression of P2X7 in human hematopoietic cell lines and leukemia patients. 1547 73

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