Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the past several years, extensive studies on the mechanisms underlying IL-4 and IL-13 signaling have enabled us to gain insight into how these cytokines regulate immune responses. Because both IL-4 and IL-13 use the IL-4Ralpha as a receptor component, these cytokines activate many common signaling pathways. Both of these cytokines use Janus kinases (JAKs) to initiate signaling and activate signal transducer and activator of transcription-6 (STAT6), which is a transcription factor required for many of their biologic functions. In addition to JAK/STAT, these cytokines also activate a variety of other signaling molecules that are important in regulating IL-4-induced proliferation and protection from apoptosis. Suppressor of cytokine signaling-1 (SOCS-1) is a molecule that can inhibit the activation of IL-4 signaling through the inhibition of JAKs. The Fes tyrosine kinase is activated by IL-4 and appears to be important in regulating IL-4-induced proliferation through the phosphorylation of insulin receptor substrate (IRS) molecules. IRS molecules are essential for IL-4-induced proliferation through their ability to recruit phosphoinositol-3 kinase to the activated IL-4 receptor kinase. In addition, IL-4 can activate a number of phosphatases including SH2-containing inositol phosphatase (SHIP), SHP-1, and SHP-2. Finally, B-cell lymphoma gene-6 (BCL-6) appears to regulate a subset of IL-4-induced genes. Thus the biologic responses induced by IL-4/IL-13 require a complex interaction of signaling pathways and regulators.
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PMID:IL-4/IL-13 signaling beyond JAK/STAT. 1085 36

Interleukin-9 (IL-9) is a Th2 cytokine whose overexpression is associated with asthma and T cell lymphomagenesis. All the IL-9 activities studied so far are mediated by a specific hemopoietin receptor that activates a Jak/STAT pathway. Searching for genes specifically modulated by IL-9, we observed that the 24P3 mRNA is strongly upregulated in BW5147 T lymphoma cells upon IL-9 stimulation. 24P3 is a member of the lipocalin family, and has been reported to bind N-formyl-Met-Leu-Phe, a potent neutrophil chemoattractant, and possibly other lipophilic mediators of inflammation. A similar 24P3 induction was observed in other T cell lymphomas (EL4 and TH201) in response to IL-9, as well as in EL4 cells stimulated with IL-6 or IL-1. By contrast, other IL-9-responsive cells such as mast cell line MC9 and B cell lymphoma A20 showed no 24P3 induction upon IL-9 stimulation. Experiments using IL-9R mutants indicated that STAT transcription factors, particularly STAT3, are involved in this process. However, 24P3 gene induction was slow, reaching a plateau from 36 to 72 hours after stimulation and was inhibited if cells were treated with cycloheximide during the first 8 hours of IL-9 stimulation, suggesting an indirect induction requiring new protein synthesis.
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PMID:Interleukin-9 induces 24P3 lipocalin gene expression in murine T cell lymphomas. 1128 60

IgE switching requires the prior induction of C epsilon germline transcripts which is mediated by the concerted binding of STAT-6 and NF kappa B to the C epsilon promoter. These transcription factors are regulated by IL-4 and CD40, respectively. However the latter can effect other signaling pathways and the present study explores the role of p38 MAPK in induction of C epsilon germline transcripts. CD40 and IL-4, both alone and in synergy, were initially shown to activate the C epsilon promoter in a B cell lymphoma cell line. Under the same conditions CD40 caused activation of p38 MAPK, whereas IL-4 was ineffective. The p38 MAPK inhibitor, SB203580, and a dominant negative form of p38 MAPK decreased the CD40 activation of the C epsilon promoter by reducing the ability of CD40 to increase the transactivation potential of NF kappa B. This study suggests that p38 MAPK is crucially important in mediating CD40 activation of NF kappa B which acts to induce C epsilon germline transcripts, ultimately facilitating IgE switching.
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PMID:CD40 employs p38 MAP kinase in IgE isotype switching. 1170 12

When cells were incubated in the presence of both interferon-gamma (IFN-gamma) and all-trans retinoic acid (ATRA), the concentration of IFN-gamma required to induce apoptosis of B-cell lymphoma cells was much lower than that required for myeloid or erythroid cell lines. The concentration of IFN-gamma that effectively inhibited the proliferation of BALM-3 cells was 1/40 of that required for BALM-1 cells. STAT-1 phosphorylation, IRF-1 mRNA and protein expression and RAR-beta expression were enhanced to a greater degree in BALM-3 cells treated with IFN-gamma and ATRA than in BALM-1 cells treated with IFN-gamma and ATRA, suggesting that these IFN-gamma related genes were involved in the induction of apoptosis of BALM-3 cells.
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PMID:Human B-cell lymphoma cell lines are highly sensitive to apoptosis induced by all-trans retinoic acid and interferon-gamma. 1219 70

Activity of Janus kinase 2 (JAK2) in the JAK2/STAT5 signaling pathway is critically controlled by suppressor of cytokine signaling-1 (SOCS-1). We have previously shown that SOCS-1 is biallelically mutated in the primary mediastinal B-cell lymphoma (PMBL) cell line MedB-1, resulting in impaired JAK2 degradation and sustained phospho-JAK2 action. SOCS-1 is frequently mutated in PMBL tumor primaries. Here, we report that the PMBL cell line Karpas1106P has a biallelic deletion of the SOCS-1 region on chromosome 16p13.13. By fluorescence in situ hybridization and microsatellite analysis, this deletion was narrowed down to a range of 650 kb to 1.48 Mb. Like MedB-1, Karpas1106P harbors gains of the JAK2 gene on chromosomal region 9p24 and elevated levels of JAK2 mRNA. Nevertheless, JAK2 protein was not increased but constitutively phosphorylated in Karpas1106P cells. In analogy to MedB-1 cells, Karpas1106P cells exhibited a retarded degradation of de novo synthesized JAK2 protein revealed by pulse/chase experiments. Therefore, we conclude that loss of SOCS-1 function either by mutation or by the complete deletion of the gene plays an important role in the dysregulation of JAK/STAT signaling in Karpas1106P and PMBL.
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PMID:Biallelic deletion within 16p13.13 including SOCS-1 in Karpas1106P mediastinal B-cell lymphoma line is associated with delayed degradation of JAK2 protein. 1628 70

Respiratory syncytial virus (RSV) is a paramyxovirus that produces airway inflammation, in part by inducing interleukin-8 (IL-8) expression, a CXC-type chemokine, via the NF-kappaB/RelA and STAT/IRF signaling pathways. In RSV-infected A549 cells, IL-8 transcription attenuates after 24 h in spite of ongoing viral replication and persistence of nuclear RelA, suggesting a mechanism for transcriptional attenuation. RSV infection induces B-cell lymphoma protein -3 (Bcl-3) expression 6 to 12 h after viral infection, at times when IL-8 transcription is inhibited. By contrast, 293 cells, deficient in inducible Bcl-3 expression, show no attenuation of IL-8 transcription. We therefore examined Bcl-3's role in terminating virus-inducible IL-8 transcription. Transient expression of Bcl-3 potently inhibited virus-inducible IL-8 transcription by disrupting both the NF-kappaB and STAT/IRF pathways. Although previously Bcl-3 was thought to capture 50-kDa NF-kappaB1 isoforms in the cytoplasm, immunoprecipitation (IP) and electrophoretic mobility shift assays indicate that nuclear Bcl-3 associates with NF-kappaB1 without affecting DNA binding. Additionally, Bcl-3 potently inhibited the STAT/IRF pathway. Nondenaturing co-IP assays indicate that nuclear Bcl-3 associates with STAT-1 and histone deacetylase 1 (HDAC-1), increasing HDAC-1 recruitment to the IL-8 promoter. Treatment with the HDAC inhibitor trichostatin A blocks attenuation of IL-8 transcription. A nuclear targeting-deficient Bcl-3 is unable to enhance HDAC-1-mediated chemokine repression. Finally, small inhibitory RNA-mediated Bcl-3 "knockdown" resulted in enhanced RSV-induced chemokine expression in A549 cells. These data indicate that Bcl-3 is a virus-inducible inhibitor of chemokine transcription by interfering with the NF-kappaB and STAT/IRF signaling pathways by complexing with them and recruiting HDAC-1 to attenuate target promoter activity.
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PMID:Respiratory syncytial virus-inducible BCL-3 expression antagonizes the STAT/IRF and NF-kappaB signaling pathways by inducing histone deacetylase 1 recruitment to the interleukin-8 promoter. 1630 1

The suppressors of cytokine signaling (SOCS) are critically involved in the regulation of cellular proliferation, survival, and apoptosis via cytokine-induced JAK/STAT signaling. SOCS-1 silencing by aberrant DNA methylation contributes to oncogenesis in various B-cell neoplasias and carcinomas. Recently, we showed an alternative loss of SOCS-1 function due to deleterious SOCS-1 mutations in a major subset of primary mediastinal B-cell lymphoma (PMBL) and in the PMBL line MedB-1, and a biallelic SOCS-1 deletion in PMBL line Karpas1106P. For both cell lines our previous data demonstrated retarded JAK2 degradation and sustained phospho-JAK2 action leading to enhanced DNA binding of phospho-STAT5. Here, we analysed SOCS-1 in laser-microdissected Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL). We detected SOCS-1 mutations in HRS cells of eight of 19 cHL samples and in three of five Hodgkin lymphoma (HL)-derived cell lines by sequencing analysis. Moreover, we found a significant association between mutated SOCS-1 of isolated HRS cells and nuclear phospho-STAT5 accumulation in HRS cells of cHL tumor tissue (P < 0.01). Collectively, these findings support the concept that PMBL and cHL share many overlapping features, and that defective tumor suppressor gene SOCS-1 triggers an oncogenic pathway operative in both lymphomas.
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PMID:Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation. 1653 38

Interleukin-6 (IL-6) affects the survival and proliferation of myeloma cells via autocrine and/or paracrine mechanisms. In this study, we investigated the effects of IL-6, IL-6 receptor antagonist (IL-6RA), and gp130 antagonist (gp130A) on the membrane expressions of IL-6R and gp130, on the viability, on the proliferation, on the DNA synthesis, and on the cell cycle phases in several multiple myeloma (MM) cell lines and B cell lymphoma cell lines. Our results showed that (1) all five MM cell lines (OPM-2, RPMI-8226, U-266, KMS-12-BM, MOLP-8) expressed surface IL-6R and gp130, the B cell lymphomas (WSU-1, DOHH-2, U-698) expressed only gp130; (2) exogenous IL-6 markedly up-regulated the expression of membrane IL-6R (up to 186%) and down-regulated the gp130 receptor (down to 4%) in MM cell lines, the membrane expression of gp130 in B cell lymphomas was not altered; (3) IL-6 markedly increased the spontaneous proliferation (up to 151%) in all MM cell lines, that of B cell lymphomas was not affected; (4) IL-6 increased the DNA synthesis in the S cell cycle phase of MM cells and arrested the stage G2/M, IL-6 was ineffective in any cell cycle phase of B cell lymphoma; (5) IL-6RA inhibited the membrane IL-6R partially, the proliferation was decreased only slightly; and (6) although gp130A inhibited the membrane gp130 completely, the proliferation was decreased 81-78% in MM and B cell lymphoma cell lines. This means that gp130 is not absolutely necessary for the cellular signalling cascade via JAK/STAT and RAS/MAPK pathways involved in proliferation and viability. Our results give an indication in the therapy of MM: IL-6 antibody (IL-6A) alone or in combination with IL-6RA. The latter could be more effective. This kind of therapy is not recommended for B cell lymphoma, as these cells have no IL-6R.
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PMID:Multiple myeloma and B cell lymphoma. Investigation of IL-6, IL-6 receptor antagonist (IL-6RA), and GP130 antagonist (GP130A) using various parameters in an in vitro model. 1689 69

Primary mediastinal B-cell lymphoma (PMBL) is an aggressive extranodal B-cell non-Hodgkin's lymphoma with specific clinical, histopathological and genomic features. To characterize further the genotype of PMBL, we analyzed 37 tumor samples and PMBL cell lines Med-B1 and Karpas1106P using array-based comparative genomic hybridization (matrix- or array-CGH) to a 2.8k genomic microarray. Due to a higher genomic resolution, we identified altered chromosomal regions in much higher frequencies compared with standard CGH: for example, +9p24 (68%), +2p15 (51%), +7q22 (32%), +9q34 (32%), +11q23 (18%), +12q (30%) and +18q21 (24%). Moreover, previously unknown small interstitial chromosomal low copy number alterations (for example, -6p21, -11q13.3) and a total of 19 DNA amplifications were identified by array-CGH. For 17 chromosomal localizations (10 gains and 7 losses), which were altered in more than 10% of the analyzed cases, we delineated minimal consensus regions based on genomic base pair positions. These regions and selected immunohistochemistries point to candidate genes that are discussed in the context of NF-kappaB transcription activation, human leukocyte antigen class I/II defects, impaired apoptosis and Janus kinase/signal transducer and activator of transcription (JAK/STAT) activation. Our data confirm the genomic uniqueness of this tumor and provide physically mapped genomic regions of interest for focused candidate gene analysis.
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PMID:Further delineation of chromosomal consensus regions in primary mediastinal B-cell lymphomas: an analysis of 37 tumor samples using high-resolution genomic profiling (array-CGH). 1772 85

STAT family members have been implicated in regulating the balance between B cell lymphoma (BCL)6 and B lymphocyte induced maturation protein (BLIMP)1 to control plasma cell differentiation. We previously showed that STAT5 induces BCL6 to block plasma cell differentiation and extend the life span of human B cells. The heterogeneity in STAT activation by cytokines and their effects on B cell differentiation prompted us to investigate the effect of STAT3 activation in plasma cell differentiation. First stimulation with IL-21, which promotes plasma cell differentiation, induced robust and prolonged STAT3 activation in primary human B cells. We then investigated effects of direct STAT3 activation on regulation of plasma cell genes, cellular phenotype, and Ig production. Activation of a tamoxifen-regulated STAT3-estrogen receptor fusion protein triggered BLIMP1 mRNA and protein up-regulation, plasma cell phenotypic features, and Ig secretion. When STAT3 was activated by IL-21 in B cells ectopically expressing BCL6, BLIMP1 was up-regulated, but only partial plasma cell differentiation was achieved. Lastly, through coexpression of BCL6 and STAT3-ER, we verified that STAT3 activation functionally mimicked IL-21 treatment and that STAT3-mediated BLIMP1 up-regulation occurred despite high BCL6 expression levels indicating that BCL6 is not the dominant repressor of BLIMP1. Thus, up-regulation of BLIMP1 alone is not sufficient for differentiation of primary human B cells into plasma cells; concomitant down-regulation of BCL6 is absolutely required for completion of the plasma cell differentiation program.
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PMID:STAT3-mediated up-regulation of BLIMP1 Is coordinated with BCL6 down-regulation to control human plasma cell differentiation. 1835 4


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