Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Continuous human leukemia-lymphoma (LL) cell lines represent a rich resource of abundant, accessible and manipulable living cells contributing significantly to a better understanding of the pathophysiology of hematopoietic tumors. In particular, classical and molecular cytogenetics have benefitted enormously from the availability of LL cell lines with specific chromosomal abnormalities. Such aberrations may be the portal to the discovery of novel oncogene rearrangements for which positive cell lines provide a resource for both discovery and functional studies. The new continuous leukemia cell line MUTZ-11 was established in 1994 from the peripheral blood of a 60-year-old woman with acute myeloid leukemia (AML) M4 (following 2 years with myelodysplastic syndromes). DNA fingerprinting confirmed the authenticity and derivation of the cell line. The immunoprofile as determined by flow cytometry was as follows: positive for myelocytic markers (CD13, CD15, CD33, CD65 and CD68), negative for T-cell (except for CD4 and CD7), B-cell and erythroid-megakaryocytic markers. The cell line is constitutively cytokine-dependent and growth depends on externally added cytokines. With regard to cytokine receptor expression, the cell line was found to be positive for GM-CSFRalpha (granulocyte-macrophage colony-stimulating factor receptor, CD116), Kit (CD117) and IL-3Ralpha (interleukin-3 receptor, CD123). The cytokine response profiles as determined by [(3)H]-thymidine incorporation assay were: 2-to-12 fold growth stimulation of MUTZ-11 by GM-CSF, IFN-alpha (interferon), IFN-beta, IFN-gamma, IL-3 and SCF (stem cell factor); growth inhibition by TGF-beta1 (transforming growth factor), TNF-alpha (tumor necrosis factor) and TNF-beta. Cytogenetic analysis showed the following consensus karyotype: 46, XX, der(16)t(16;17)(p13.3;q23)x2. Previous molecular biological analysis documented that MUTZ-11 cells carry both an FLT3 internal tandem duplication (ITD) and an MLL partial tandem duplication (PTD). The scientific significance of MUTZ-11 lies (i). in the absolute cytokine-dependency and the proliferative response to various cytokines, (ii). in the unique cytogenetic (disomic t(16;17)) and (iii). molecular biological alterations (FLT3 ITD + MLL PTD). In summary, the new cytokine-dependent AML-derived cell line MUTZ-11 displays unique novel features and emphasizes the need for comprehensive analysis of new LL cell lines which may lead to the discovery of important pathogenetic alterations.
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PMID:New cytokine-dependent acute myeloid leukemia cell line MUTZ-11 with disomic chromosome rearrangement t(16;17). 1506 4

Thalidomide and its immunomodulatory (IMiDs) analogs (lenalidomide, Revlimid, CC-5013; CC-4047, ACTIMID) are a novel class of compounds with numerous effects on the body's immune system, some of which are thought to mediate the anticancer and anti-inflammatory results observed in humans. Thalidomide is currently being used experimentally to treat various cancers and inflammatory diseases. It is approved for the treatment of dermal reaction from leprosy and is currently in phase III trials for multiple myeloma. Thalidomide and IMiDs inhibit the cytokines tumor necrosis factor-alpha (TNF-alpha), interleukins (IL) 1beta, 6, 12, and granulocyte macrophage-colony stimulating factor (GM-CSF). They also costimulate primary human T lymphocytes inducing their proliferation, cytokine production, and cytotoxic activity thereby increasing the T cells' anticancer activity. They induce an IL-2-mediated primary T cell proliferation with a concomitant increase in IFN-gamma production and decrease the density of TNF-alpha-induced cell surface adhesion molecules ICAM-1, VCAM-1, and E-selectin on human umbilical vein endothelial cells. Thalidomide stimulates the Th-1 response increasing IFN-gamma levels while CC-4047 increased IL-2 as well. Some of the above immunomodulatory activities along with anti-angiogenic, anti-proliferative, and pro-apoptotic properties are thought to mediate the IMiDs' antitumor responses observed in relapsed and refractory multiple myeloma and some solid tumor cancers. This has led to their use in various oncology clinical trials. The second generation IMiD, lenalidomide, has shown potential in treating the bone marrow disorders myelodysplastic syndrome and multiple myeloma. It is currently in phase II and III trials for these diseases respectively with numerous phase II trials in other hematologic and solid tumors.
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PMID:Properties of thalidomide and its analogues: implications for anticancer therapy. 1614 35

Down syndrome (DS) patients are frequently complicated with infections, autoimmune phenomena and hematological disorders, including transient abnormal myelopoiesis (TAM) in infancy and acute megakaryoblastic leukaemia (AMKL) in later life. In this study, serum levels of cytokines from 23 TAM and 15 AMKL patients were examined using the highly sensitive microsphere fluorescence system. Statistical differences between DS neonates with or without TAM were found in IL-1beta [median 7.0 pg/ml (0.34-271.6) verses 0.05 pg/ml (0.0-2.4), p=0.034], TNF-alpha [8.11 pg/ml (0.1-253.0) verses 0.41 pg/ml (0.1-1.5), p=0.041], and IFN-gamma [20.0 pg/ml (0.14-406.3) verses 1.5 pg/ml (0.14-5.79), p=0.036]. Moreover, abnormal inflammatory cytokinemia was also found in myelodysplastic syndrome (MDS) and AMKL with DS. These abnormal cytokinemia may have a role in the pathophysiology of TAM, MDS and AMKL in DS, especially in liver fibrosis or myelofibrosis.
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PMID:Pro-inflammatory cytokinemia is frequently found in Down syndrome patients with hematological disorders. 1705 49

Dendritic cells (DC) are pivotal for T cell-mediated immunity. We investigated the early and terminal maturation of monocyte-derived DC (MoDC) in myelodysplastic syndromes (FAB subtypes refractory anemia (MDS-RA) or refractory anemia with ringed sideroblasts (MDS-RARS)). Immature MoDC were obtained by culture of monocytes with GM-CSF and IL-4 for 8 days. To obtain mature MoDC, TNF-alpha was added during the final three culture days. T cell proliferation and T cell cytokine secretion in mixed lymphocyte reactions (MLR) unveiled a strong reduction of allostimulatory capacity of mature but also of immature MoDC from MDS patients. Immature MoDC from MDS patients exhibited an almost normal immunophenotype, but secreted substantially less IL-12 and more IL-10 in response to LPS/IFN-gamma than normal controls. Terminal addition of TNF-alpha to GM-CSF/IL-4 treated monocytes failed to extinguish cytokine production by MDS MoDC and failed to induce the expected membrane upregulation of costimulatory and other ligands as in normal controls. While our data provide further support for previous studies that have indicated an impaired differentiation of immature towards mature MoDC, they also clearly demonstrate a qualitatively and quantitatively altered cytokine secretion at the level of immature MoDC, which may in part explain the reduced allostimulatory capacity of these cells. These alterations may contribute to immune modulation of the clinical phenotype of marrow failure in MDS, and may have to be considered when designing DC-based immunotherapeutic strategies for MDS.
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PMID:Immature and mature monocyte-derived dendritic cells in myelodysplastic syndromes of subtypes refractory anemia or refractory anemia with ringed sideroblasts display an altered cytokine profile. 1718 53


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