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

There is an increasing interest on one of the smallest human chromosomes as it is shown by the First International Symposium on the Human Chromosome 20 and by the genetic map prepared by EUROGEN. The conserved part of the long arm of human chromosome 20 is synthenic with the distal part of the mouse chromosome 2 allowing for some analogies between them. Human chromosome 20 contains several important genes for the human pathology. Mutations of one of them, the vasopressin-neurophysin II gene, are responsible for hereditary neurohypophyseal diabetes insipidus. Severe combined immunodeficiency due to adenosin deaminase deficiency is the first human disorder successfully treated by somatic gene therapy. Spongiform encephalopathies are related to mutation and/or polymorphisms of the PRNP amyloid gene. One form of benign familiar neonatal convulsions is mapped to a specific locus on chromosome 20. In some families, maturity onset diabetes of the young (MODY) is caused by alterations of a hypothetical gene closely linked to the ADA locus. Allegile syndrome is often associated with deletions and microdeletions of the short arm of the chromosome. Finally, deletions of the long arm of the chromosome is a frequent finding in several hematologic malignities, specifically in myeloproliferative disorders and myelodysplastic syndromes.
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PMID:[The human genome--chromosome 20]. 748 83

Mitoxantrone (Mito) is presently used in an increasing number of malignancies including leukemias, breast carcinomas and solid tumors. With it has come increased incidence of post remission cytopenias and delayed engraftment following autologous bone marrow transplantation (ABMT). We evaluated engraftment in 18 patients who underwent allogeneic BMT (allo-BMT) following a preparative regimen that included high dose Mito (60 mg m2). Sixteen patients with malignant disease (AML 10, ALL 3, CML 2, MDS 1) and two with non-malignant disease (SCID 1, osteopetrosis 1) underwent non-T cell depleted allo-BMT. Fourteen patients with malignancies were transplanted at an advanced stage of disease while only two patients were standard risk patients. Of the 18 patients, 12 were females and six males, with a median age of 30.5 (0.3-48) years. Nine patients, (breast cancer 3, malignant lymphoma 4 and AML 2), who underwent ABMT following preparative regimens with comparable doses of Mito, served as controls. Engraftment following allo-BMT was normal and not statistically different from engraftment following ABMT. Five patients, who underwent allo-BMT, developed >grade II acute graft versus host disease (GVHD) and two developed chronic GVHD. After a median follow up of 28 (6-42) months, five patients are alive (one with disease). In summary, engraftment following high dose Mito and allo-BMT is not statistically different from engraftment following ABMT. Controlled studies with a larger group of standard risk patients are needed to elucidate the role of Mito in conditioning regimens pre-BMT.
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PMID:Engraftment following mitoxantrone (Mito) based conditioning for allogeneic bone marrow transplantation (allo-BMT). 961 12

A transgenic SCID (TG-SCID) mouse expressing the human cytokines interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) has been generated with the aim of making a model system allowing the in vivo proliferation of human hematopoietic cells. Using TG-SCID mice expressing high levels (30-35 ng/ml in the serum) of human GM-CSF and IL-3, we attempted to engraft a human myeloid leukemia cell line, F-36P, derived from a myelodysplastic syndrome (MDS) patient. When F-36P cells were transferred intravenously into sublethally irradiated TG-SCID mice, extensive proliferation of F-36P cells was found 4-6 wk later. Successful engraftment, however, required the preadministration of a monoclonal antibody to mouse interleukin-2 receptor (IL-2R) beta chain, neutralizing NK activity. Surprisingly, all the transplanted TG-SCID mice engrafted with F-36P cells developed hind leg paralysis approximately 6 wk after transfer. Histological analysis demonstrated extensive invasion and formation of osteolytic lesions by the F-36P cells in the vertebrae. These data indicate that transgenic SCID mice expressing human IL-3 and GM-CSF provide a useful system for the study of human leukemia. In addition, NK cells appear to play an important role in rejection of human cells.
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PMID:Engraftment of human myelodysplastic syndrome derived cell line in transgenic severe combined immunodeficient (TG-SCID) mice expressing human GM-CSF and IL-3. 971 20

Stem cell transplantations were performed in 69 children at Siriraj Hospital over a ten year period. The source of stem cells was bone marrow (60), peripheral blood (3), or cord blood (6). The diseases treated included 35 thalassemias, 11 Burkitt's lymphoma, five non-Hodgkin's lymphoma, five aplastic anemia, eight acute leukemia, and one each of neuroblastoma, severe combined immunodeficiency, Wiskott-Aldrich syndrome, myelodysplastic syndrome, and pyruvate kinase deficiency. The success rate of stem cell transplantation in Thai children varied according to the underlying diseases of the patients, ranging from 50% in acute leukemia to 100% in aplastic anemia. The outcome of stem cell transplantation in 35 thalassemic children revealed 23 (79.4%) were cured, whereas three (10.3%) remain alive with disease and the other three (10.3%) died. The incidence of graft-versus-host disease was low hen compared with that of Western countries. It is concluded that bone marrow, peripheral blood and cord blood stem cell transplantation will be the treatment of choice and will be widely used in the future to cure many hematologic and malignant disorders in children.
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PMID:Bone marrow, peripheral blood and cord blood stem cell transplantation in children: ten years' experience at Siriraj Hospital. 988 40

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders characterized by ineffective hematopoiesis and frequent progression to acute myeloid leukemia. Within MDS, 5q- syndrome constitutes a distinct clinical entity characterized by an isolated deletion of the long arm of chromosome 5 (5q-), a relatively good prognosis, and infrequent transformation to acute leukemia. The cell of origin in 5q- syndrome as well as in other 5q-deleted MDS patients has not been established, but evidence for involvement of multiple myeloid (but not lymphoid) lineages has suggested that a myeloid-restricted progenitor rather than a pluripotent (lympho-myeloid) stem cell might be the primary target in most patients. Although in 9 patients no evidence of peripheral blood T-cell and only 1 case of B-cell involvement was found, the data herein support that 5q deletions occur in hematopoietic stem cells (HSCs) with a combined lympho-myeloid potential. First, in all investigated patients a minimum of 94% of cells in the minor CD34(+)CD38(-) HSC compartment were 5q deleted as determined by fluorescence in situ hybridization. Second, in 3 of 5 patients 5q aberrations were detected in a large fraction (25% to 90%) of purified CD34(+)CD19(+) pro-B cells. Furthermore, extensive functional characterization with regard to responsiveness to early-acting cytokines, long-term culture-initiating cells, and nonobese diabetic/severe combined immunodeficiency repopulating cells supported that MDS HSCs in 5q-deleted patients are CD34(+)CD38(-), but inefficient at reconstituting hematopoiesis.
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PMID:Isolation and characterization of hematopoietic progenitor/stem cells in 5q-deleted myelodysplastic syndromes: evidence for involvement at the hematopoietic stem cell level. 1097 41

Using a model of experimental leukemia in mice, we have demonstrated that tumor development depends upon interactions between preleukemic cells and their microenvironment whose functions are altered. Cytokine injections inhibit tumor development by inducing a functional restoration of this environment. Human myelodysplastic syndromes (MDS) are marrow pathologies considered as preleukemic stages. As in murine leukemias, it is possible that marrow environment could play a key role in their evolution. We currently establish a model of human hematopoiesis in NOD/SCID mice grafted with human bone fragments. We hope that this model would allow to analyse the role of the marrow stromal cells in MDS and to establish treatments restoring their functions.
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PMID:[Preleukemic states: an experimental murine model for myelodysplastic human syndromes]. 1169 89

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, APO2L) has been shown to induce apoptosis in a number of tumor cell lines as well as in some primary tumors whereas cells from most normal tissues are highly resistant to TRAIL-induced apoptosis. We have studied the susceptibility of primary malignant and normal bone marrow hematopoietic progenitors to TRAIL-induced apoptosis. Extracellular domain of human TRAIL with N-terminal His(6) tag (His-TRAIL, amino acids 95-281) was produced in E. coli and its apoptosis-inducing ability was compared with the leucine-zipper containing TRAIL, LZ-TRAIL. Both variants of TRAIL had the same apoptosis-inducing ability. Clonogenic progenitor assays showed that His-TRAIL significantly reduced the number of myeloid colonies (CFU-GM) and clusters from patients with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndromes (MDS). His-TRAIL had no negative effect on the number of CFU-GM colonies and clusters derived from bone marrow cells of AML patients in complete remission, and lymphoma patients without bone marrow involvement, as well as those derived from normal cord blood cells. Moreover, we found that normal human stem cells treated with high doses of His-TRAIL maintain a repopulating potential when transplanted into NOD/SCID mice. To conclude, our data document that TRAIL does not affect normal human hematopoiesis but suppresses the growth of early primary leukemia and myelodysplasia progenitors.
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PMID:TRAIL (Apo2L) suppresses growth of primary human leukemia and myelodysplasia progenitors. 1184 Feb 65

Clonality studies of mature cells suggest that the primary transformation event in myelodysplastic syndrome (MDS) most frequently occurs in a myeloid-restricted progenitor, a hypothesis supported by recent studies of purified CD34(+)Thy1(+) hematopoietic stem cells (HSCs) in cases with trisomy 8 (+8). In contrast, we recently demonstrated that a lymphomyeloid HSC is the target for transformation in MDS cases with del(5q), potentially reflecting heterogeneity within MDS. However, since +8 is known to frequently be a late event in the MDS transformation process, it remained a possibility that CD34(+)CD38(-)Thy1(+) HSC disomic for chromosome 8 might be part of the MDS clone. In the present studies, although a variable fraction of CD34(+)CD38(-)Thy1(+) cells were disomic for chromosome 8, they did not possess normal HSC activity in long-term cultures and nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice. Mixing experiments with normal CD34(+)CD38(-) cells suggested that this HSC deficiency was intrinsic and not mediated by indirect mechanisms. Furthermore, investigation of 4 MDS cases with combined del(5q) and +8 demonstrated that the +8 aberration was always secondary to del(5q). Whereas del(5q) invariably occurs in CD34(+)CD38(-)Thy-1(+) HSCs, the secondary +8 event might frequently arise in progeny of MDS HSCs. Thus, CD34(+)CD38(-)Thy1(+) HSCs are invariably part of the MDS clone also in +8 patients, and little HSC activity can be recovered from the CD34(+) CD38(-)Thy1(+) HSC. Finally, in advanced cases of MDS, the MDS reconstituting activity is exclusively derived from the minor CD34(+)CD38(-) HSC population, demonstrating that MDS stem cells have a similar phenotype as normal HSCs, potentially complicating the development of autologous transplantation for MDS.
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PMID:Involvement and functional impairment of the CD34(+)CD38(-)Thy-1(+) hematopoietic stem cell pool in myelodysplastic syndromes with trisomy 8. 1207 35

Sublethally irradiated NOD/SCID mice were transplanted with hematopoietic progenitor cells obtained from the marrow of patients with myelodysplastic syndromes (MDS). Engraftment of MDS cells, as determined by flow cytometry, was delayed compared to marrow from normal donors. Human CD38(+)CD34(-) cells were prominent in marrows and spleens of MDS chimeras. CD34(+)CD38(-), CD34(+)CD38(+) and T cells were also easily detected. Human myeloid cells (CD33(+); CD15(+)) were present in low proportions. No clonal precursors were identified by fluorescent in situ hybridization (FISH) or by molecular analysis of polymorphic X-linked markers in mice with documented engraftment of human cells more than 2 months after transplantation. These data indicate that human cells present in murine MDS chimeras, at the levels of sensitivity of our assays, were derived from residual normal cells in human MDS marrow, and suggest that the NOD/SCID environment was not conducive to the expansion of clonal MDS precursors. This model may allow identification of factors relevant for sustaining or expanding clonal precursors.
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PMID:NOD/SCID mice transplanted with marrow from patients with myelodysplastic syndrome (MDS) show long-term propagation of normal but not clonal human precursors. 1262 Feb 94

Patients with acute myelogenous leukemia or myelodysplastic syndrome may respond to farnesyl transferase inhibitors (FTIs) with partial or complete response rates noted in about 30% of such patients. FTIs prevent the attachment of a lipid farnesyl moiety to dependent proteins prior to their insertion into the plasma membrane and thereby prevent activity of these prenylation-dependent proteins, but their mechanism of tumor suppression remains unknown. Many patients receiving FTIs do experience myelosuppression. In this work, the in vitro effects of the FTI, R115777 on normal and leukemic hematopoiesis have been examined as have its effects on apoptosis induction and cell cycle profile in both leukemic blasts and normal CD34+ cells. R115777 was inhibitory to normal CD34+ cell proliferation and to leukemic blast cells, but did not affect long-term culture initiating cell frequency nor NOD-SCID reconstituting capacity. No induction of apoptosis or cell cycle changes were noted in AML blasts. These data suggest that myelosuppression with R115777 occurs largely at the intermediate to late progenitor stage of hematopoiesis and that cyclic use might avoid long-term marrow suppression.
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PMID:Effects of the farnesyl transferase inhibitor R115777 on normal and leukemic hematopoiesis. 1297 Jul 80


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