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)

We evaluated the effects of transforming growth factor-beta 1 (TGF-beta 1) on the growth of hematopoietic progenitors in normal donors and in patients with hematologic malignancies now designed as clonal disorders of multipotential stem cells. TGF-beta 1 at 80 pM exhibited differential effects on the normal hematopoietic progenitors when cells were stimulated with different growth factors, such as G-CSF, GM-CSF, interleukin-3 (IL-3), or stem cell factor (SCF). The suppressive effect by TGF-beta 1 was increased for growth with GM-CSF, IL-3, and SCF, and growth with G-CSF was unaffected in hematologic malignancies, TGF-beta 1 suppression for growth with G-CSF was increased for essential thrombocythemia (ET) and polycythemia vera; chronic myelogenous leukemia (CML) in chronic phase; CML in accelerated phase; CML in myeloid crisis; myelodysplastic syndrome (MDS) in refractory anemia; MDS in refractory anemia with an excess of blasts; and acute myeloblastic leukemia (AML). In CML-myeloid crisis and AML, TGF-beta 1 almost completely abolished the growth, with some patient-to-patient variation. The mean ED50s for the growth of leukemic blast progenitors were 1.6, 1.2, 0.7, and 0.2 pM in the presence of G-CSF, GM-CSF, IL-3, and SCF, respectively, c-myc and c-myb antisense oligonucleotides significantly suppressed the growth of leukemic blast progenitors, but not that of clonogenic cells from normal donors and patients with ET. We also demonstrated that TGF-beta 1 inhibits mRNA expression by AML blasts for c-myc and/or c-myb. When the data are taken together, growth suppression by TGF-beta 1 appears to increase with the progression of clonal evolution in hematologic malignancies.
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PMID:Differential effects of TGF-beta 1 on normal and leukemic human hematopoietic cell proliferation. 754 18

beta ig-h3 is a novel gene first discovered by differential screening of a cDNA library made from A549 human lung adenocarcinoma cells treated with transforming growth factor-beta 1 (TGF-beta 1). It encodes a 683-amino-acid protein containing a secretory signal sequence and four homologous internal domains. Here we show that treatment of several types of cells, including human melanoma cells, human mammary epithelial cells, human keratinocytes, and human fibroblasts, with TGF-beta resulted in a significant increase in beta ig-h3 RNA. A portion of the beta ig-h3 coding sequence was expressed in bacteria, and antisera against the bacterially produced protein was raised in rabbits. This antisera was used to demonstrate that several cell lines secreted a 68-kD beta IG-H3 protein after treatment with TGF-beta. Transfection of beta IG-H3 expression plasmids into Chinese hamster ovary (CHO) cells led to a marked decrease in the ability of these cells to form tumors in nude mice. The beta IG-H3 protein was purified from media conditioned by recombinant CHO cells, characterized by immunoblotting and protein sequencing and shown to function in an anti-adhesion assay in that it inhibited the attachment of A549, HeLa, and WI-38 cells to plastic in serum-free media. Sequencing of cDNA clones encoding murine beta ig-H3 indicated 90.6% conservation at the amino acid level between the murine and human proteins. Finally, the beta ig-h3 gene was localized to human chromosome 5q31, a region frequently deleted in preleukemic myelodysplasia and leukemia. The corresponding mouse beta ig-h3 gene was mapped to mouse chromosome 13 region B to C1, which confirms a region of conservation on human chromosome 5 and mouse chromosome 13. We suggest that this protein be named p68 beta ig-h3.
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PMID:beta ig-h3: a transforming growth factor-beta-responsive gene encoding a secreted protein that inhibits cell attachment in vitro and suppresses the growth of CHO cells in nude mice. 802 1

The role of positive and negative cytokine interactions in G1 cell cycle regulation of haemopoietic cells was analysed by determination of the expression patterns of D-type cyclins and cyclin-dependent kinases (cdks) in SKM-1 myelodysplastic syndrome (MDS) cells incubated with granulocyte-macrophage colony-stimulating factor (GM-CSF) and/or transforming growth factor-beta 1 (TGF-beta 1). TGF-beta 1 inhibited SKM-1 cell proliferation due to the cell cycle arrest in G1 phase. GM-CSF abrogated the TGF-beta 1-mediated G1 arrest in these cells. Reverse transcription-polymerase chain reaction (RT-PCR) analysis indicated that TGF-beta 1-mediated G1 arrest correlated with the down-regulation of cdk4, cdk6 and cyclin D2, and that abrogation of TGF-beta 1-mediated G1 arrest by GM-CSF correlated with the constitutive over-expression of cyclin D2 and cdk6 but not cdk4. These results suggest the importance of cyclin D2/cdk6 levels in abrogating G1 arrest in cells exposed to TGF-beta 1, and raise the possibility that the GM-CSF-mediated up-regulatory pathway of signal transduction through cyclin D2/cdk6 differs from the TGF-beta 1-cdk4-mediated pathway in SKM-1 cells. This signal transduction pathway through cyclin D2/cdk6 might play an important role in haemopoietic regulation by the cytokine network.
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PMID:Granulocyte-macrophage colony-stimulating factor abrogates transforming growth factor-beta 1-mediated cell cycle arrest by up-regulating cyclin D2/Cdk6. 933 4

Myelodysplastic syndromes (MDS) are clonal disorders, which frequently undergo leukemic transformation. It was recently shown that the promoter of the p15INK4b but not the p16INK4a gene is frequently and selectively hypermethylated in MDS. The p15INK4b gene is a cyclin dependent kinase inhibitor gene, which is actively transcribed after TGFbeta exposure. Methylation of the p15INK4b gene is significantly correlated with blastic bone marrow involvement, and sequential analyses have shown that methylation increases with disease evolution toward AML. These data strongly suggest that p15INK4b gene methylation is a mechanism allowing leukemic cells to escape to inhibitory signals from the bone marrow environment, however the exact role of p15INK4b gene methylation in disruption of the signal mediated by TGFbeta remains to be investigated.
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PMID:P15INK4b gene methylation and myelodysplastic syndromes. 1060 81

Labeling index (LI), apoptosis, levels of 2 pro-apoptotic cytokines tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta(TGF-beta), and the number of monocyte/macrophage cells that are the likely source of the cytokines were simultaneously measured in plastic-embedded bone marrow (BM) biopsy sections of 145 patients with myelodysplastic syndromes (MDS). TNF-alpha was correlated with TGF-beta (P = .001) and with monocyte/macrophage cells (P = .003). Patients with excess blasts in their marrows had a higher TGF-beta level (P = .01) and monocyte/macrophage number (P = .05). In a linear regression model,TGF-beta emerged as the most significant biological difference between patients who have excess of blasts and those who do not (P = .01). We conclude that in addition to TNF-alpha, TGF-beta also plays a significant role in the initiation and pathogenesis of MDS, and that a more precise definition of its role will likely identify better preventive and therapeutic strategies.
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PMID:Biological significance of proliferation, apoptosis, cytokines, and monocyte/macrophage cells in bone marrow biopsies of 145 patients with myelodysplastic syndrome. 1199 58

Myelodysplastic syndromes are clonal diseases of the hematopoietic stem cell with normal or increased bone marrow cellularity and peripheral cytopenias. Pathophysiology of these diseases is complex with frequent ras mutations, a growth defect of immature progenitors mainly erythroid progenitors, and increased apoptosis of differentiated cells. This growth defect could be linked to (1) a resistance to hematopoietic cytokine stimulation although, erythropoietin receptor expression and functionality are normal and/or (2) increased susceptibility to apoptosis due to overexpression of the death domain receptor Fas on CD34+, CD33+ and GPA+ cells. Stromal cells are thought to produce increased quantities of inhibitory cytokines such as TNF-alpha, TGF-beta, IFN gamma et IL-1. Better understanding of MDS pathophysiology is required for applying adequate therapy either blocking apoptosis or stimulating hematopoiesis.
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PMID:[Physiopathology of myelodysplastic syndromes]. 1208 71

Bone marrow (BM) fibrosis could occur secondarily to several clinical disorders: hematological and nonhematological. Clinical presentation of fibrosis could occur in myeloproliferative diseases, lymphoma, myelodysplastic syndrome and myeloma. The pathophysiology underlying BM fibrosis remains unclear despite intensive study, with a corresponding lack of specific therapy. This review discusses new insights in the role of substance P, cytokines and fibronectin in the development of BM fibrosis. Substance P is a neuropeptide that possesses pleiotropic properties, e.g. neurotransmission and immune/hematopoietic modulation and is linked to BM fibrosis. Cytokines and growth factors, in particular those associated with fibrogenic properties, e.g. TGF-beta, IL-1 and platelet-derived growth factor, are linked to BM fibrosis. Extracellular matrix proteins are increased in patients with BM fibrosis. Fibronectin in the sera of patients with BM fibrosis is complexed to substance P. Fibronectin appears to protect substance P from degradation by endogenous peptidases. This review describes the preliminary findings on the colocalization of substance P and fibronectin in the BM of patients with fibrosis. These data are reviewed in the context of published reports with particular focus on the relevant cytokines. A more detailed understanding of intra- and intercellular mechanisms in BM fibrosis may lead to effective therapy.
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PMID:Substance p-fibronectin-cytokine interactions in myeloproliferative disorders with bone marrow fibrosis. 1248 16

We investigated the cause of myelofibrosis and proliferation of megakaryocytes in myelodysplastic syndrome with myelofibrosis (MDS-MF (+)). Plasma-transforming growth factor-beta1 (PTGF-beta1) concentrations closely correlated with myelofibrosis grade in MDS-MF (+) and were higher than those in idiopathic myelofibrosis (IMF), essential thrombocythemia (ET), idiopathic thrombocytopenic purpura (ITP), MDS-without MF (MDS-MF (-)) or healthy volunteers (HV). Peripheral blood mononuclear cells from MDS-MF (+) patients expressed more TGF-beta1 mRNA than those from IMF, MDS-MF (-) or HV. When we immunostained bone marrow specimens of MDS-MF (+) for TGF-beta, the intensity of blasts was apparently higher than that of megakaryocytes, while in MDS-MF (-), megakaryocytes were immunostained with a similar intensity as that in MDS-MF (+), but blasts were negative for staining. In IMF, megakaryocytes, monocytes and small mononuclear cells representing CD34+ cells were all similarly stained with a much lower intensity than that of blasts in MDS-MF (+). The number of bone marrow megakaryocytes were increased the most in MDS-MF (+), followed by ET, ITP, MDS-MF (-) and NHL and correlated with plasma thrombopoietin (TPO) levels or with plasma TGF-beta1 levels, respectively, in each disease. Thus, in MDS-MF (+), both myelofibrosis and the increased megakaryocytes were ascribed to overproduction of TGF-beta1 from blasts.
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PMID:Involvement of transforming growth factor-beta and thrombopoietin in the pathogenesis of myelodysplastic syndrome with myelofibrosis. 1603 67

Myelodysplastic syndromes (MDS) are clonal stem cell disorders that lead to ineffective hematopoiesis and are common causes of low blood counts in the elderly. The exact molecular mechanisms regulating increased stem apoptosis in these disorders are not well defined. p38 MAPK activation is important in regulating the growth inhibitory signals of TNF-alpha, TGF-beta and Interferons on human hematopoiesis. Our findings show that p38 MAPK is overactivated in myelodysplasia bone marrows and regulates hematopoietic stem cell apoptosis. Inhibition of p38 MAPK by genetic or pharmacologic means decreases apoptosis and stimulates in vitro hematopoiesis from primary MDS hematopoietic progenitors. These studies point to the potential efficacy of selective p38alpha inhibitor, SCIO-469, in human bone marrow failure.
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PMID:p38 MAP kinase regulates stem cell apoptosis in human hematopoietic failure. 1735 44

Extramedullary hematopoiesis (EMH) is a relatively rare, but well-documented, manifestation of chronic myeloproliferative disorders. Microscopically, foci of EMH consist of erythroid and myeloid precursors intermixed with megakaryocytes. It typically occurs in the spleen and liver, but very occasionally manifests as cutaneous EMH. We report a 76-year-old Japanese man with cutaneous EMH arising from myelodysplastic syndrome associated with myelofibrosis. His cutaneous manifestations showed multiple skin-colored firm nodules over the head, trunk, and extremities. We detected high plasma levels of transforming growth factor (TGF)-beta1 in our patient. Immunohistochemical analysis of the skin biopsy sample revealed TGF-beta1 overexpression in immature hematopoietic cells and dermal fibroblasts within the cutaneous EMH mass of the dermis. These findings suggest that TGF-beta could play some role in the onset of cutaneous EMH. Five months after his first visit to our dermatologic clinic, the patient developed bone-marrow failure and died. Based on our observations, accelerated malignancy in the bone marrow should be considered in any patient with cutaneous EMH. It is presumed that TGF-beta released from hematopoietic cells within the cutaneous EMH play a critical role in the activation of hematologic malignancy.
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PMID:Transforming growth factor-beta overexpression in cutaneous extramedullary hematopoiesis of a patient with myelodysplastic syndrome associated with myelofibrosis. 1834 20


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