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  • MALIGNANCIES  (5)
  • 1
    Keywords: CANCER ; CELLS ; EXPRESSION ; CELL ; Germany ; neoplasms ; GENE ; GENE-EXPRESSION ; GENES ; transcription ; cell line ; MESSENGER-RNA ; primary ; recombination ; SEQUENCE ; SEQUENCES ; TARGET ; LYMPHOMA ; MALIGNANCIES ; UP-REGULATION ; CELL-LINE ; LINE ; LYMPHOCYTES ; INSTABILITY ; SOMATIC HYPERMUTATION ; B-CELL LYMPHOMA ; GENOMIC INSTABILITY ; HIGH-LEVEL ; MALIGNANCY ; ONCOLOGY ; RE ; COSTIMULATION ; LEVEL ; AID ; USA ; GERMINAL-CENTER ; B-LYMPHOCYTES ; cancer research ; HODGKIN LYMPHOMA ; genomic ; B-CELL ; LIMIT ; ACCESSIBILITY ; DIVERSIFICATION ; CLASS SWITCH RECOMBINATION ; SWITCHES ; ANTIBODY DIVERSIFICATION ENZYME ; CLASS-SWITCH RECOMBINATION ; DNA DEAMINATION ; HIGH-LOAD ; mediastinal B-cell lymphoma
    Abstract: Activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) and class switch recombination (CSR) in activated B lymphocytes and is potentially implicated in genomic instability of B-cell malignancies. For unknown reasons, B-cell neoplasms often lack SHM and CSR in spite of high MD expression. Here, we show that primary mediastinal B-cell hTnphoma (PMBL), an immunoglobulin (Ig)-negative lymphoma that possesses hypermutated, class-switched Ig aenes. expresses high levels of AID with an intact primary structure but does not do CSR in 14 of 16 cases analyzed. Absence of CSR coincided with low Ig germ-line transcription, whereas high level germ-line transcription was observed only in those two cases with active CSR. Interleukin-4/CD40L costimulation induced CSR and a marked up-regulation of,germ-line transcription in the PMBL-derived cell line MedB-1. In the PMBL cell line Karpas 1106P, CSR was not inducible and germ-line transcription remained low on stimulation. However, Karpas 1106P, but not MedB-1, had ongoing SHM of the Ig gene and BCL6. These genes were transcribed in Karpas 1106P, whereas transcription was undetectable or low in MedB-1 cells. Thus, accessibility of the target sequences seems to be a major limiting factor for AID-dependent somatic gene diversification in PMBL
    Type of Publication: Journal article published
    PubMed ID: 17638864
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  • 2
    Keywords: CANCER ; EXPRESSION ; CELL ; Germany ; GENE ; HYBRIDIZATION ; DNA ; INDEX ; tumour ; CONTRAST ; chromosome ; virus ; IN-SITU ; COMPARATIVE GENOMIC HYBRIDIZATION ; cytogenetics ; LYMPHOMA ; MALIGNANCIES ; NUMBER ; leukemia ; ABERRATIONS ; IN-SITU HYBRIDIZATION ; MORPHOLOGY ; ABNORMALITIES ; FLUORESCENCE ; IMBALANCES ; C-MYC ; INTERPHASE ; EPSTEIN-BARR-VIRUS ; B-CELL LYMPHOMA ; Bcl-2 ; chemoresistance ; F ; CHROMOSOMAL BREAKPOINTS ; Epstein-Barr virus ; FEATURES ; immunohistology ; molecular cytogenetics ; sporadic and endemic Burkitt's lymphoma ; TRANSLOCATIONS
    Abstract: The present study has compared immunohistological marker expression profiles and genomic imbalances in seven African endemic Burkitt's lymphomas (eBLs) with those in ten European B-cell lymphomas with MYC rearrangement as shown by fluorescence in situ hybridization (FISH) analysis. eBLs showed a typical histomorphology and a homogeneous immuno-profile: CD10+, CD38+, CD77+, bcl-2-, and IgM+. Epstein-Barr virus (EBV) DNA was present in all cases. On comparative genomic hybridization (CGH), only three out of six eBLs showed imbalances (median number of imbalances = 2), with gains on chromosome 17 in two eBLs. The European lymphomas were all highly proliferating, with a Ki-67 index of at least 90%, and included seven with morphology typical of sporadic Burkitt's lymphoma (sBL) and three immunoblastic diffuse large B-cell lymphomas with MYC rearrangement (MYC re+DLBCL). In contrast to eBL, the immuno-profiles of the European lymphomas were less homogeneous and inconsistent for CD10, CD38, CD77, IgM and bcl-2 expression. EBV DNA was not detected. In five of seven sBLs, CGH showed a higher number of imbalances (median = 6), with recurrent gains on chromosome 1q (3/7) and losses on 12q and 17p (2/7), whereas all three MYC re+DLBCLs had fewer imbalances (median = 4), with gains on 17q in two of three lymphomas. It is concluded that eBL has a homogeneous immunohistology and few secondary genomic aberrations, whereas MYC-rearranged and highly proliferating European B-cell lymphomas are a heterogeneous group that includes sBL and a subgroup of diffuse large B-cell lymphomas. Copyright (C) 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley Sons, Ltd
    Type of Publication: Journal article published
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  • 3
    Keywords: CELLS ; EXPRESSION ; proliferation ; BLOOD ; DISEASE ; DISTINCT ; GENE ; HYBRIDIZATION ; PROTEIN ; SAMPLES ; transcription ; ACCUMULATION ; NF-KAPPA-B ; ACTIVATION ; ALPHA ; TARGET ; AMPLIFICATION ; chromosome 2 ; COMPARATIVE GENOMIC HYBRIDIZATION ; COPY NUMBER ; COPY-NUMBER ; cytogenetics ; immunohistochemistry ; LYMPHOMA ; MALIGNANCIES ; NUCLEAR-FACTOR ; PATTERNS ; REED-STERNBERG CELLS
    Abstract: Structural aberrations of the short arm of chromosome 2, mostly resulting in gains of 2p13similar to16, have recently been described as being highly recurrent in Hodgkin and Reed- Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL). As these gains consistently lead to increased copy numbers of the REL oncogene locus, we investigated the expression of the c-Rel protein in a series of 30 cHL cases with known genomic REL status as determined by comparative genomic hybridization and interphase cytogenetics. Expression of the c-Rel protein was investigated in 26 biopsies by immunohistochemistry. Distinct patterns were observed in HRS cells with no staining, cytoplasmic, and/or nuclear staining for c-Rel. All 13 samples with additional copies of the REL locus displayed nuclear staining for c-Rel, while 13 cHL samples lacking chromosome 2 (2p) gains displayed a significantly lower proportion or complete absence of HRS cells with nuclear c-Rel expression. Detailed analysis using combined immunophenotyping and interphase cytogenetics of individual HRS cells demonstrated that REL gains correlated with the-presence of nuclear c-Rel staining. Additionally, in 2 cHL samples with translocation breakpoints in 2p13similar to16, nuclear staining of c-Rel was observed; in one of them the staining pattern was indicative of a truncated c-Rel protein. The correlation between structural aberrations involving the REL locus and nuclear c-Rel accumulation in HRS cells qualifies REL as a target gene of the frequent gains in 2p in cHL. The data suggest that REL aberrations are a genetic mechanism contributing to constitutive nuclear factor (NF)-kappaB/Rel activation in cHL. (C) 2003 by The American Society of Hematology
    Type of Publication: Journal article published
    PubMed ID: 12511414
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  • 4
    Keywords: CELLS ; EXPRESSION ; Germany ; POPULATION ; SITE ; GENE ; PROTEIN ; MONOCLONAL-ANTIBODY ; TISSUE ; recombination ; T-CELLS ; immunohistochemistry ; MALIGNANCIES ; B-CELLS ; PHENOTYPE ; RT-PCR ; ANTIBODY-RESPONSES ; MALIGNANCY ; thymus ; SUBSET ; LEVEL ; LYMPHOMAS ; lymph node ; LYMPH-NODE ; INDUCED CYTIDINE DEAMINASE ; IMMUNOGLOBULIN CLASS-SWITCH
    Abstract: Neoplastic transformation of mature B cells can be triggered by class-switch recombination of the immunoglobulin gene, which aberrantly targets a protooncogene and promotes translocation. Class-switch recombination is initiated by the B-cell-specific protein activation-induced cytidine deaminase (AID). Using immunohistochemistry with a newly generated monoclonal antibody and quantitative reverse-transcription-polymerase chain reaction (RT-PCR) on microdissected tissue from lymph node, tonsil, and thymus, we demonstrate that AID expression is found in secondary lymphoid organs outside germinal centers and in the thymic medulla at substantial levels. This is accompanied by the presence of circle transcripts, indicating class-switch recombination to be active at these sites. The dominant AID-expressing cell population outside germinal centers displays cytomorphologic properties corresponding to those that define the recently characterized interfollicular large B-cell subset. These findings indicate that interfollicular large B cells and AID-expressing B lymphocytes of the thymic medulla could give rise to mature B-cell malignancies
    Type of Publication: Journal article published
    PubMed ID: 16269615
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  • 5
    Keywords: CANCER ; EXPRESSION ; Germany ; PATHWAY ; GENE ; LINES ; TRANSDUCTION ; ACTIVATION ; COMPLEX ; IDENTIFICATION ; MALIGNANCIES ; REED-STERNBERG CELLS ; systems biology ; JAK2 ; STAT5
    Abstract: Primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL) share a frequent constitutive activation of Janus-activated kinase (JAK) / signal transducer and activator of transcription (STAT) signaling pathway. Due to complex non-linear relations within the pathway, key dynamic properties remained to be identified to predict possible strategies for intervention. We report the development of dynamic pathway models based on quantitative data collected on signaling components of JAK/STAT pathway in two lymphoma-derived cell lines, MedB-1 and L1236, representative of PMBL and cHL, respectively. We show that the amounts of STAT5 and STAT6 are higher whereas those of SHP1 are lower in the two lymphoma cell lines compared to normal B cells. Distinctively, L1236 cells harbor more JAK2 and less SHP1 molecules per cell than MedB-1 or control cells. In both lymphoma cell lines we observe interleukin-13 (IL13)-induced activation of interleukin-4 receptor alpha, JAK2 and STAT5, but not of STAT6. Genome-wide, 11 early and 16 sustained genes are up-regulated by IL13 in both lymphoma cell lines. Specifically, the known STAT-inducible negative regulators CISH and SOCS3 are up-regulated within 2 hours in MedB-1 but not in L1236 cells. Based on this detailed quantitative information we established two mathematical models, MedB-1 and L1236 model, able to describe the respective experimental data. Most of model parameters are identifiable and therefore the models are predictive. Sensitivity analysis of the model identifies six possible therapeutic targets able to reduce gene expression levels in L1236 cells and three in MedB-1. We experimentally confirm reduction in target gene expression in response to inhibition of STAT5 phosphorylation, thereby validating one of the predicted targets.
    Type of Publication: Journal article published
    PubMed ID: 21127196
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