MedB-1, a human tumor cell line derived from a primary mediastinal large B-cell lymphoma

Möller, Peter; Brüderlein, Silke; Sträter, Jörn; Leithäuser, Frank; Hasel, Cornelia; Bataille, Frauke; Moldenhauer, Gerhard; Pawlita, Michael; Barth, Thomas F.E.

doi:10.1002/ijc.1211

Cited by 29 publications

(34 citation statements)

References 39 publications

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“…The MedB-1 cell line has been described previously. 11 Adherent peripheral blood mononuclear cells (PBMCs) obtained from healthy donors after informed consent were differentiated into macrophages as in Perez-Bercoff et al 12 and into immature DCs (iDCs) using GM-CSF and IL4 as previously described. 13 Mature dendritic cells (mDCs) were obtained by 24-hour incubation with different stimulating cocktails: 10 ng/mL TNF␣ ϩ 3 g/mL PGE 2 , 1.5 g/mL CD40L with or without 1000 UI/mL IFN␥, 20 ng/mL LPS, or 10 g/mL poly-IC.…”

Section: Transfection and Cell Culturementioning

confidence: 99%

Human IL4I1 is a secreted l-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation

Boulland

Marquet

Molinier‐Frenkel

et al. 2007

Blood

154

177

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Interleukin-4-induced gene 1 (IL4I1) was first described as a B-cell IL4-inducible gene and is highly expressed in primary mediastinal B-cell lymphomas. We established stable HEK293 clones expressing human and mouse IL4I1 to examine their biochemical properties and function. Both proteins were secreted into the culture medium, and we observed the secretion of endogenous human IL4I1 (hIL4I1) protein in a mediastinal lymphoma B-cell line, MedB-1. We showed that IL4I1 has L-amino acid oxidase activity, optimal at physiological pH and primarily directed toward phenylalanine. Immunohistochemical analysis of secondary lymphoid organs showed staining of germinal center macrophages and inflammatory myeloid cells. In vitro, functional enzyme was highest in mature dendritic cells (DCs), suggesting a role in antigenpresenting cell/T-lymphocyte cross-talk. Indeed, hIL4I1 inhibited the proliferation of CD3-stimulated T lymphocytes with a similar effect on CD4 ؉ and CD8 ؉ T cells. IntroductionInterleukin-4 (IL4) is the master cytokine for T-helper type 2 (Th2) lymphocyte differentiation and function. Along with its important role in B-lymphocyte stimulation by T-helper cells in germinal centers of secondary lymphoid organs, it also regulates the growth and function of many different cell types of the immune system. 1 IL4 transcriptional effects are primarily mediated by the signalization and transcription factor 6 (STAT6), which is responsible for the induction and repression of multiple target genes. 2 An immediate-early IL4-inducible gene called interleukin fourinduced gene 1 (FIG1/IL4I1) has first been described in the mouse 3 and subsequently characterized in human B cells. 4 IL4I1 mRNA expression is restricted to lymphoid tissues, with the highest levels found in lymph nodes and spleen. 4,5 IL4-activated murine B cells express IL4I1 within 2 hours of stimulation. We have demonstrated that high levels of expression of this gene are characteristic of primary mediastinal large B-cell lymphoma (PMBL), a specific subtype of diffuse large B-cell lymphoma. 5 The high expression of IL4I1 by PMBL may result from the constitutive activation of STAT6 in these tumors. 6 Both human and mouse IL4I1 mRNA sequences encode a protein containing a putative signal peptide indicative of potential secretion and a large central domain, highly homologous to flavin-containing amino acid oxidases. 3,4 While sharing high similarity over the majority of the sequence (547 amino acids of the 567 in the human sequence), the human and mouse proteins diverge substantially at their C-terminal region. 4 The IL4I1 protein shares the highest similarity with proteins presenting L-amino acid oxidase (LAAO) activity, such as snake venom LAAO,7,8 and mouse milk LAAO. 9 Recently, Mason et al have demonstrated that mouse IL4I1 (mIL4I1) possesses an LAAO activity toward aromatic amino acids. The enzyme was mostly active at acidic pH, in contrast to other known members of the LAAO family, and its expression was restricted primarily to lysosomes. 10 In this work, w...

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Section: Transfection and Cell Culturementioning

confidence: 99%

Human IL4I1 is a secreted l-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation

Boulland

Marquet

Molinier‐Frenkel

et al. 2007

Blood

154

177

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“…11,13 Fluorescence in situ hybridization Establishing of the BAC clones RP11-39K24 and RP11-81F1 (RZPD GmbH, Berlin, Germany) spanning the JAK2 and SOCS-1 locus, respectively, and fluorescence in situ hybridization (FISH) were performed according to standard protocols. 14 Reverse transcription and real-time PCR Total RNA was isolated using the RNeasy kit (Qiagen, Hilden, Germany) and treated with RNase-free DNase (Roche, Mannheim, Germany).…”

Section: Cell Culturementioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

“…5 Frequent loss of heterocygosity of chromosomal region 16p13. 13, including the SOCS-1 locus, has been described in hepatocellular carcinoma. 6 Moreover, epigenetic silencing of SOCS-1 by CpGmethylation has been found in myeloid leukemia, mantle cell lymphoma, follicular lymphoma and myeloma and tumor progression was shown to be related to constitutive activation of the JAK/ STAT signaling pathway.…”

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confidence: 99%

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Biallelic deletion within 16p13.13 including SOCS‐1 in Karpas1106P mediastinal B‐cell lymphoma line is associated with delayed degradation of JAK2 protein

Melzner

Weniger

Bucur

et al. 2005

Intl Journal of Cancer

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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. ' 2005 Wiley-Liss, Inc.Key words: SOCS-1; JAK/STAT signaling; Karpas1106P; mediastinal B-cell lymphomaThe Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is induced by several cytokines and growth factors. 1 Kinase activity of JAK2 and subsequent activation of downstream targets such as STATs are negatively regulated by suppressor of cytokine signaling (SOCS) proteins. 2 SOCS proteins are composed of a family of 8 members sharing a central Src-homology 2 (SH2) domain and a highly conserved C-terminal domain termed SOCS box. 3 Binding of SOCS-1 via its SH2 region to the catalytic center of phospho-JAK2 inhibits the kinase activity of the JAK2 protein and, as a consequence, tyrosine-phosphorylated JAK2 and STATs are greatly reduced. 4 A further function of SOCS-1 is accomplished by its SOCS box domain, which associates with the elongins B and C to the elongin BC complex, leading to proteasomal degradation of both SOCS protein and its target. 5 Frequent loss of heterocygosity of chromosomal region 16p13.13, including the SOCS-1 locus, has been described in hepatocellular carcinoma. 6 Moreover, epigenetic silencing of SOCS-1 by CpGmethylation has been found in myeloid leukemia, mantle cell lymphoma, follicular lymphoma and myeloma and tumor progression was shown to be related to constitutive activation of the JAK/ STAT signaling pathway. [7][8][9] We have recently shown that the primary mediastinal B-cell lymphoma (PMBL) cell line MedB-1 has biallelic loss of function mutations of SOCS-1, which lead to decelerated JAK2 degradation and, hence, sustained phospho-JAK2 action. This classified SOCS-1 as a novel tumor suppressor gene. 10 Furthermore, we found SOCS-1 mutations in about half of PMBL.Karpas1106P, another PMBL cell line, exhibits an immunophenotype and cytogenet...

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“…However, extensive studies of MAL protein expression in normal lymphoid tissues and lymphoid malignancies have not been performed yet. The aims of our study were first to analyze the pattern of MAL expression in peripheral blood lymphocytes and normal lymphoid tissues, including the thymus, tonsil, reactive lymph node, and spleen and secondarily, to further extend the immunohistochemical analysis of MAL protein expression to a large series of B-and T-cell lymphoid malignancies and to the primary mediastinal large B-cell lymphomaderived B-cell line MedB-1 (15).…”

mentioning

confidence: 99%

MAL Expression in Lymphoid Cells: Further Evidence for MAL as a Distinct Molecular Marker of Primary Mediastinal Large B-Cell Lymphomas

et al. 2002

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MedB-1, a human tumor cell line derived from a primary mediastinal large B-cell lymphoma

Cited by 29 publications

References 39 publications

Human IL4I1 is a secreted l-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation

Human IL4I1 is a secreted l-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation

Biallelic deletion within 16p13.13 including SOCS‐1 in Karpas1106P mediastinal B‐cell lymphoma line is associated with delayed degradation of JAK2 protein

MAL Expression in Lymphoid Cells: Further Evidence for MAL as a Distinct Molecular Marker of Primary Mediastinal Large B-Cell Lymphomas

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