Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0023418 (leukemia)
93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Murine acquired immunodeficiency syndrome (MAIDS) is caused by exposure to murine leukemia virus and serves as a model to study human AIDS. In MAIDS-susceptible C57BL/6 mice, virus exposure leads to progressive immune deficiency, while resistant strains such as BALB/c recover from infection and develop protective immunity. The goal of this study was to identify early gene expression patterns that may be important in establishing this strain-specific differential response. Total RNA was isolated from spleens and pooled lymph nodes of both mouse strains at 3 and 7 days post virus infection. The complementary DNA generated from this RNA was hybridized to mouse oligonucleotide DNA microarrays using a strategy that controlled for inherent variability and highlighted only virus-induced changes. Fluorescent intensities were normalized and analyzed for statistically significant differential expression between strains across both time points and lymphoid organs. The majority of the resistance-associated genes was identified at day 3 post-infection and demonstrated the highest fold differences between strains, while more susceptibility-associated sequences were seen at 7 days post-infection. Among the most highly differentially expressed sequences seen at the earlier time point were genes related to protein metabolism, especially serine proteases. Differential patterns of chemokine-related genes were observed at the later time point. The overall pattern of expression suggests strain-specific differences in proteases and chemokines within secondary lymphoid organs shortly after infection influence the likelihood of disease progression.
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PMID:MAIDS resistance-associated gene expression patterns in secondary lymphoid organs. 1861 34

The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4, participate in the retention of acute myeloblastic leukemia (AML) cells within the bone marrow microenvironment and their release into the circulation. AML cells also constitutively express SDF-1-dependent elastase, which regulates their migration and proliferation. To study the molecular events and genes regulated by the SDF-1/CXCR4 axis and elastase in AML cells, we examined gene expression profiles of the AML cell line, U937, under treatment with a neutralizing anti-CXCR4 antibody or elastase inhibitor, as compared with non-treated cells, using DNA microarray technology. Unsupervised hierarchical clustering analysis demonstrated similar gene expression profiles of anti-CXCR4 antibody or elastase inhibitor-treated cells, as compared with control. Pathway and functional analysis showed a greater tendency toward differentiation in cells under either one of both treatment modalities. Thus given, we further analyzed the effects of CXCR4 inhibition on AML cell growth and differentiation using the antagonist AMD3100. AMD3100 arrested proliferation in AML cell lines and triggered changes that mimicked differentiation, including morphological changes and the expression of myeloid differentiation antigens. Inhibition of elastase also triggered the differentiation of AML cells. Our study defines a new role for the SDF-1/CXCR4 axis in the regulation of leukemic cell survival and differentiation.
Leukemia 2008 Dec
PMID:The CXCR4 antagonist AMD3100 impairs survival of human AML cells and induces their differentiation. 1876 46

Berberine plays a prominent role on the control of tumor cell invasion and migration. SDF-1 is a homeostatic chemokine that signals through CXCR4 which is expressed by hematopoietic tumor cells. The SDF-1/CXCR4 axis is involved in the migration process of leukemic cells. In this study, we investigated the effects of berberine on the SDF-1-induced HL-60 cells, primary acute myeloid leukemia (AML) cells and leukemic stem cells (LSCs) migration. Transwell migration chambers (8 microm) were used to assess the role of berberine on leukemic cell migration; Flow cytometry was used to analyze the role of berberine on the CXCR4 expression; SDF-1 protein level secreted by bone marrow stromal cells (BMSCs) was evaluated by ELISA. Results demonstrated that berberine could partly inhibit SDF-1-induced AML cells as well as LSCs migration. Berberine could reduce SDF-1 protein level secreted by BMSCs in the microenvironment but not affect CXCR4 expression on HL-60 cell membrane, and we hypothesized that berberine could inhibit AML cells migration partly by reducing the secreting of SDF-1 by BMSCs and inhibiting HERG1 K(+) channels of leukemic cells. Therefore, it is speculated that berberine might be a potentially effective agent for prevention of leukemia.
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PMID:Berberine inhibits SDF-1-induced AML cells and leukemic stem cells migration via regulation of SDF-1 level in bone marrow stromal cells. 1880 69

The World Health Organization classification of mature T-cell lymphoproliferative disorders, combines clinical, morphological and immunophenotypic data. The latter is a major contributor to the classification, as well as to the understanding of the malignant T-cell behavior. The fact that T-cell migration is regulated by chemokines should, in theory, enable us to identify tissue tropism and organ involvement by neoplastic T-cells by monitoring chemokine receptor surface expression. To address this issue we compared the expression of several early and late inflammatory, homeostatic, and organ specific chemokine receptors on blood T-cells from normal individuals and patients with T-cell large granular lymphocytic leukemia and peripheral T-cell lymphoma. T-cell large granular lymphocytic leukemia cells mainly express late inflammatory chemokine receptors (CXCR1 and CXCR2), whereas peripheral T-cell lymphoma cells usually express one or more organ homing receptors (CCR4, CCR6 and CCR7). Nevertheless, no clear correlation was found between CCR4 and CCR7 expression and skin and lymph node involvement, respectively. Compared to their normal counterparts, lymphoma T-cells displayed an exaggerated CCR4 expression, whereas leukemic T-cells had abnormally high CXCR1 and CXCR2 expression. Further analysis revealed that, in leukemia patients, the percentage of neoplastic cells expressing CCR5 correlates directly with lymphocytosis. In addition, in the case of CD8 T-cell leukemia patients, an inverse correlation with neutropenia was found. In lymphoma patients, higher CCR4 and CCR7 expression is accompanied by lower to absent CCR5 expression.
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PMID:Chemokine receptor repertoire reflects mature T-cell lymphoproliferative disorder clinical presentation. 1884 29

Host dendritic cells (DCs) play a critical role in initiating graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL), and separation of GVL from GVHD remains a major challenge in the treatment of hematologic malignancies by allogeneic hematopoietic cell transplantation (HCT). Here, we show that preconditioning with anti-CD3 monoclonal antibody before conditioning with total body irradiation (TBI) prevents GVHD but retains GVL in a HCT model of major histocompatibility complex (MHC)-mismatched C57BL/6 donor to BALB/c host. Prevention of GVHD is associated with inhibition of donor T-cell expression of homing and chemokine receptors, and inhibition of GVHD target tissue expression of chemokines. Furthermore, inhibition of donor T-cell expression of gut homing alpha4beta7 and chemokine receptor (CCR)9 by anti-CD3 preconditioning results from a reduction of CD103(+) DCs in draining mesenteric lymph nodes (LNs), which is associated with down-regulation of DC expression of CCR7, a receptor required for tissue DC migration to draining LNs. These results indicate that anti-CD3 preconditioning reduces not only tissue release of chemokines but also prevents tissue DC migration to draining LNs and subsequently reduces the capacity of DCs of draining LNs to imprint donor T-cell tissue tropism. Therefore, modulation of host DCs by anti-CD3 preconditioning before HCT represents a new approach for separating GVL from GVHD.
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PMID:Anti-CD3 preconditioning separates GVL from GVHD via modulating host dendritic cell and donor T-cell migration in recipients conditioned with TBI. 1892 52

Human T lymphocytes express both ionotropic and metabotropic glutamate receptors that control immune responses, cell activation, maturation and death. In this study, we examined the effect of N-methyl-D-aspartate (NMDA) and sigma1-receptor ligands on the secretion of the proinflammatory chemokine interleukin 8 (IL-8) and the anti-inflammatory cytokine interleukin 10 (IL-10) in human leukemia Jurkat cells and peripheral blood lymphocytes (PBLs). We have shown that NMDA increased IL-8 and decreased IL-10 secretion and that sigma-ligands modulated the action of NMDA. Moreover, the effects of NMDA and sigma-ligands were interrelated with the nitric oxide (NO) content, suggesting that the intracellular concentration of NO could play a major role in the synthesis of cytokines. Western blots against the NR2A and NR2B subunits of the NMDA glutamate receptor revealed that long-term (48 h) treatment of PBLs with glutamate at concentrations within normal plasma levels (1 x 10(-5)M), in contrast to low concentrations (0.3 x 10(-6)M), downregulates the NR2A subunit, probably by internalization. Furthermore, we found that PBLs with noninternalized NR2A secreted less IL-10 than lymphocytes with downregulated NR2A; under these conditions, the transcriptional activity of NF-kappaB was increased whereas the transcriptional activity of c-Fos was decreased. These findings implicate that the activities of NF-kappaB and c-Fos control the expression of the IL8 and IL10 genes, depending on the subunit composition of the NMDA receptor. In conclusion, we suggest that lymphocytes express an active NMDA receptor only in a low-glutamate milieu.
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PMID:N-methyl-D-aspartate and sigma-ligands change the production of interleukins 8 and 10 in lymphocytes through modulation of the NMDA glutamate receptor. 1924 43

The mechanisms regulating the migration of leukaemic cells between the blood and bone marrow compartments remain obscure, but are of fundamental importance for the dissemination of the disease. This study investigated the in vivo homing of human B cell progenitor acute lymphoblastic leukaemia (ALL) cells to the femoral bone marrow of non-obese diabetic severe combined immunodeficient (NOD/SCID) mice. It was demonstrated that patient ALL cells use the chemokine axis, chemokine (CXC motif) receptor 4 (CXCR4)/ chemokine (CXC motif) ligand 12 (CXCL12), to home to the femoral marrow. CXCL12-mediated signalling through p38 mitogen-activated protein kinase (MAPK) was required for optimal homing. In contrast, the homing of normal peripheral blood CD34(+) cells and the cytokine-dependent CD34(+) cell line Mo7e was independent of p38MAPK, consistent with the dependence of these cells, as well as normal CD34(+) CD19(+) B cell progenitors, on PI-3K/AKT signalling. Altogether, our data provide clarification of the direct role of CXCL12 in the bone marrow homing of ALL cells and demonstrate unique signalling molecule usage that may have therapeutic implications for this disease.
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PMID:CXCR4 mediates the homing of B cell progenitor acute lymphoblastic leukaemia cells to the bone marrow via activation of p38MAPK. 1934 5

Antigen-specific T cells play a key role in cellular immune response against cancer. The ability to isolate, maintain, and characterize tumor-specific T cells is a prerequisite to studying anticancer immune response and developing novel strategies for cancer immunotherapy. However, the life span of human T cells in vitro is usually short and is limited by the onset of cellular senescence. To establish long-term, antigen-specific T-cell lines and clones, we selectively immortalized antigen-responsive T cells from human peripheral blood mononuclear cells (PBMCs). PBMCs were stimulated with antigens, and then infected with a murine leukemia virus-based retroviral vector carrying an immortalizing gene, the human telomerase-reverse transcriptase gene. Since such vectors can only integrate in dividing cells, only antigen-activated T cells are efficiently transduced. Using this approach, we generated immortalized T-cell lines that maintained strictly IL-2-dependent growth and MHC-restricted, antigen-specific responsiveness, some of which have been in continuous culture for longer than 1 year, far in excess of the survival of parallel control nonimmortalized cultures. These lines showed antigen-specific proliferation with induced cytokine and chemokine production, and, in the case of CD8+ T-cell lines, antigen-specific cytolytic activity. When applied to the tumor antigen-specific T cells, the approach provides a convenient, reproducible means for generating a stable, continuously renewable source of antigen-specific T lymphocytes for a variety of studies on anticancer immunity.
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PMID:Selective immortalization of tumor-specific T cells to establish long-term T-cell lines maintaining primary cell characteristics. 1934 96

Zebrafish CXC-64, a chemokine representing a superfamily of chemotactic cytokines present in fish, is involved in recruitment, activation, and response to inflammatory stimulation. We cloned and sequenced the genomic DNA of the zebrafish CXC-64 chemokine; it was most similar to CXCL11 from humans and CXCL10 from a catfish. The zebrafish CXC-64 gene is approximately 4.0 kb long and has a four-exon, three-intron structure common to the human CXCL11 gene. However, the promoter region includes a typical TATA box and multi-transcription factor-binding sequences. To understand the roles of lipopolysaccharide (LPS), poly I:poly C, and tumor necrosis factor (TNF)-alpha in regulating zebrafish CXC-64 expression, serial deletions were made in the promoter region of this clone. Different fragments of the zebrafish CXC-64 5'-flanking region were transfected into RAW264.7 (mouse macrophage; Abelson murine leukemia virus transformed) and zfl (zebrafish liver) cells and then treated with 0, 10, 50, 100, and 200 ng/ml LPS, poly I:poly C, or TNF-alpha. The results showed that the promoter activity presented dose-dependent effects in LPS-treated RAW264.7 cells, TNF-alpha-treated RAW264.7 cells, and LPS-treated zfl cells. These results reveal that the zebrafish CXC-64 chemokine gene promoter region can be induced by LPS in both human and fish cell lines, which suggests that it plays an important role in regulating LPS.
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PMID:Organization and promoter analysis of the zebrafish (Danio rerio) chemokine gene (CXC-64) promoter. 1938 48

Human umbilical cord blood (HUCB) provides a source of progenitors for cell therapy. We isolated and characterized an HUCB-derived population of progenitors (HUCBNP), differentiated toward neuronal phenotype by human neuroblastoma-conditioning medium (CM) and nerve growth factor (NGF), which have been found to confer neuroprotection toward hypoxia-mediated neuronal injury. This study investigated whether interferon-gamma (IFN-gamma) contributes to HUCBNP differentiation. IFN-gamma was detected in the CM used for the induction of differentiation of HUCBNP and a neutralizing antibody of IFN-gamma significantly inhibited either IFN-gamma or CM-induced differentiation. Transcriptome analysis of CM-differentiated HUCBNP, identified 86 genes as highly upregulated, among them 25 were IFN-induced (such as 2',5'-oligoadenylate synthetase 1 and 2, IFN-induced protein and transmembrane proteins, STAT1 (IFN-gamma-receptor signal transducer and activator of transcription) and chemokine C-X-C motif ligand 5). Treatment of HUCBNP with human recombinant IFN-gamma, inhibited cell proliferation in a dose-dependent manner. IFN-gamma (1-100 ng/ml) enhanced neuronal differentiation, expressed by neurite outgrowths and increased expression of the neuronal markers beta-tubulin III, microtubule-associated protein 2, neuronal nuclei, neurofilament M and neuronal-specific enolase. IFN-gamma additively cooperated with NGF to induce the differentiation of HUCBNP. These data indicate that IFN-gamma promotes neuronal differentiation of HUCB-derived progenitors, proposing its use in future protocols towards cell therapy.
Leukemia 2009 Oct
PMID:Interferon-gamma-induced neuronal differentiation of human umbilical cord blood-derived progenitors. 1945 27


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