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)

The aim of the review is to summarize current knowledge concerning active immunotherapy in leukemia. The molecular mechanisms and selected clinical implications of different cancer vaccines used in pediatric and adult leukemias are discussed. Escape of neoplasmatic cells from elimination by host cells can be caused by immunological disturbances, such as the production of immunosuppressive cytokines and downregulation of costimulatory and adhesion molecules. Cells of acute lymphoblastic leukemia and chronic lymphocytic leukemia can be induced into antigen-presenting cells with the CD40 ligation system. After CD40 stimulation, leukemic cells achieve the phenotypic and functional characteristics of dendritic cells. In many studies it was confimed that these cells stimulate auto- and/or allogeneic T-cell response. Immunological response can be of cellular and humoral origin and is extensively examined. Similar effects using different cytokines such as GM-CSF, TNF-alpha, and IL-4 can be observed in acute myeloid leukemia and myelodysplastic syndromes. Clinical experience with such vaccines is limited, but the results of some preliminary reports are quite promising. Cancer vaccines are safe, result in host response, and probably prolong patients survival.
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PMID:[Experimental and selected clinical aspects of active immunotherapy in leukemia]. 1688 8

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

Accelerated programmed cell death or apoptosis appears to play an important role in the pathogenesis of myelodysplasia. As overexpression of TNF-alpha has been described to induce cell death in myelodysplasia, treatment with anti-TNF-alpha is currently being explored. Caution is needed because of an increased risk of opportunistic infection during anti-TNF-alpha treatment. We here describe a patient who was treated with anti-TNF-alpha for low risk myelodysplasia and died of invasive mucormycosis.
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PMID:Mucormycosis in a patient with low risk myelodysplasia treated with anti-TNF-alpha. 1719 57

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

We report here a 57-year-old man treated with etanercept for 6 months for psoriasis who developed myelodysplasia with acute myeloid leukemia. Leukemia cells had distinct karyotype associated with poor prognosis. The patient did not respond to cytosine arabinoside 100 mg/m(2) continuous infusion over 7 days with daunorubicin 45 mg/m(2) daily for 3 days. He also did not respond to salvage induction therapy with gemtuzumab (6 mg/m(2) on day 1 and 4 mg/m(2) on day 8) and intravenous continuous infusion cytosine arabinoside 200 mg/m(2). We review other cases of lymphoma and leukemia associated with tumor necrosis factor inhibitors and suggest mechanisms by which inhibition of the TNF-alpha family may predispose to cancer. We also suggest that all patients being considered for TNF-alpha treatment be screened for hematologic malignancies or premalignancies with blood counts and bone marrow aspirates/biopsies if indicated.
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PMID:TNF-alpha inhibitor etanercept and hematologic malignancies: report of a case and review of the literature. 1831 33

Lenalidomide (Revlimid; CC-5013) and pomalidomide (CC-4047) are IMiDs proprietary drugs having immunomodulatory properties that have both shown activity in cancer clinical trials; lenalidomide is approved in the United States for a subset of MDS patients and for treatment of patients with multiple myeloma when used in combination with dexamethasone. These drugs exhibit a range of interesting clinical properties, including anti-angiogenic, anti-proliferative, and pro-erythropoietic activities although exact cellular target(s) remain unclear. Also, anti-inflammatory effects on LPS-stimulated monocytes (TNF-alpha is decreased) and costimulatory effects on anti-CD3 stimulated T cells, (enhanced T cell proliferation and proinflammatory cytokine production) are observed. These drugs also cause augmentation of NK-cell cytotoxic activity against tumour-cell targets. Having shown that pomalidomide confers T cell-dependent adjuvant-like protection in a preclinical whole tumour-cell vaccine-model, we now show that lenalidomide and pomalidomide strongly inhibit T-regulatory cell proliferation and suppressor-function. Both drugs inhibit IL-2-mediated generation of FOXP3 positive CTLA-4 positive CD25high CD4+ T regulatory cells from PBMCs by upto 50%. Furthermore, suppressor function of pre-treated T regulatory cells against autologous responder-cells is abolished or markedly inhibited without drug related cytotoxicity. Also, Balb/C mice exhibit 25% reduction of lymph-node T regulatory cells after pomalidomide treatment. Inhibition of T regulatory cell function was not due to changes in TGF-beta or IL-10 production but was associated with decreased T regulatory cell FOXP3 expression. In conclusion, our data provide one explanation for adjuvant properties of lenalidomide and pomalidomide and suggest that they may help overcome an important barrier to tumour-specific immunity in cancer patients.
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PMID:The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells. 1900 91

Feline leukemia virus (FeLV) clone33 was obtained from a domestic cat with acute myeloid leukemia (AML). The long terminal repeat (LTR) of this virus, like the LTRs present in FeLV from other cats with AML, differs from the LTRs of other known FeLV in that it has 3 tandem direct 47-bp repeats in the upstream region of the enhancer (URE). Here, we injected cats with FeLV clone33 and found 41% developed myelodysplastic syndromes (MDS) characterized by peripheral blood cytopenias and dysplastic changes in the bone marrow. Some of the cats with MDS eventually developed AML. The bone marrow of the majority of cats with FeLV clone33 induced MDS produced fewer erythroid and myeloid colonies upon being cultured with erythropoietin or granulocyte-macrophage colony-stimulating factor (GM-SCF) than bone marrow from normal control cats. Furthermore, the bone marrow of some of the cats expressed high-levels of the apoptosis-related genes TNF-alpha and survivin. Analysis of the proviral sequences obtained from 13 cats with naturally occurring MDS reveal they also bear the characteristic URE repeats seen in the LTR of FeLV clone33 and other proviruses from cats with AML. Deletions and mutations within the enhancer elements are frequently observed in naturally occurring MDS as well as AML. These results suggest that FeLV variants that bear URE repeats in their LTR strongly associate with the induction of both MDS and AML in cats.
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PMID:Myelodysplastic syndromes and acute myeloid leukemia in cats infected with feline leukemia virus clone33 containing a unique long terminal repeat. 1903 58

Immunemediated hematopoietic suppression has been considered as one of significant pathophysiological changes in less-advanced myelodysplastic syndrome (MDS). To explore deviation of T cell subsets and its relationship to marrow cells apoptosis, measurement of helper-T (Th)/cytotoxic-T (Tc) subsets as well as the deviation situation within this two subsets (Th1/Th2 and Tc1/Tc2) in marrow was performed by flow cytometry from 39 MDS patients and 13 normal controls. Interferon (INF)-gamma and tumor necrosis factor (TNF)-alpha in marrow serum was simultaneously detected by ELISA (enzyme-linked immunosorbent assay). Furthermore, apoptosis rate of marrow cells was demonstrated by TUNEL (TdT-mediated dUTP nick end labeling). Results showed that Th and Tc subsets were unevenly activated, both deviating to type I response, which was especially obvious in patients with RCMD (according to WHO classification) and in lower-risk cases defined by International Prognosis Scoring System (IPSS). Level of INF-gamma/TNF-alpha in MDS marrow serum was markedly elevated, and so did the apoptosis rate of marrow cells. Although type I deviation was observed both in Th and Tc subsets, just Th1 cell percentage showed positive correlation with level of INF-gamma/TNF-alpha and apoptotic index of nucleated cells. In addition, cytokines level in marrow serum presented positive correlation to apoptosis. We then deduced that the increased Th1 cells in marrow may account for nucleated cells apoptosis in MDS through overproduced proapoptotic cytokines such as INF-gamma and TNF-alpha. Our results suggested that type I deviation of T cell subsets may play a role in pantocytopenia in MDS and the deviation pattern may be as a direct and effective parameter to predict response of immunosuppression therapy.
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PMID:Deviation of type I and type II T cells and its negative effect on hematopoiesis in myelodysplastic syndrome. 1904 14

Besides their role as potent antigen-presenting cells, myeloid dendritic cells (MDCs), but not plasmacytoid dendritic cells (PDCs), have been reported to have cytotoxic or cytostatic activity on some tumor cells. In this article, we analyzed the tumoristatic potential of a distinct peripheral blood monocyte-derived MDC subset which co-expressed PDC-specific marker CD123. CD123(+) MDCs represented a subset of small-sized DCs and accounted for 45-60% of peripheral blood monocytes cultured with granulocyte-macrophage colony-stimulating factor and interleukine-4 (IL-4) for 7 d. They exhibited more significant antiproliferative activity toward hematological tumor cell lines of Jurkat, HL60, and myelodysplastic syndromes over-leukemia than CD123(-) MDCs even at a low effecter/target ratio. Pretreatment of MDC and their supernatant with TRAIL-R2:Fc significantly reduced the tumoristatic effect of CD123(+) MDCs but not of CD123(-) MDCs and their supernatant. CD123(+) MDCs expressed higher level of cytoplasmic TNF-alpha-related apoptosis-inducing ligand (TRAIL) than CD123(-) MDCs, whereas both expressed very little surface and soluble TRAIL. These results reveal that CD123(+) cells represented a predominant subset of MDCs generated from peripheral blood monocytes in vitro, characterized by their potential tumoristic activity partially via cytoplasmic TRAIL.
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PMID:A subset of myeloid dendritic cells derived from peripheral blood monocytes represented a predominant subset characterized by their potential tumor-inhibiting activity. 1928 61


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