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  • DKFZ Publication Database  (6)
  • 1
    Abstract: Constitutive activation of the antiapoptotic nuclear factor-kappaB (NF-kappaB) signaling pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL). Recurrent oncogenic mutations are found in the scaffold protein CARMA1 (CARD11) that connects B-cell receptor (BCR) signaling to the canonical NF-kappaB pathway. We asked how far additional downstream processes are activated and contribute to the oncogenic potential of DLBCL-derived CARMA1 mutants. To this end, we expressed oncogenic CARMA1 in the NF-kappaB negative DLBCL lymphoma cell line BJAB. By a proteomic approach we identified recruitment of beta-catenin and its destruction complex consisting of APC, AXIN1, CK1alpha and GSK3beta to oncogenic CARMA1. Recruitment of the beta-catenin destruction complex was independent of CARMA1-BCL10-MALT1 complex formation or constitutive NF-kappaB activation and promoted the stabilization of beta-catenin. The beta-catenin destruction complex was also recruited to CARMA1 in ABC DLBCL cell lines, which coincided with elevated beta-catenin expression. In line, beta-catenin was frequently detected in non-GCB DLBCL biopsies that rely on chronic BCR signaling. Increased beta-catenin amounts alone were not sufficient to induce classical WNT target gene signatures, but could augment TCF/LEF-dependent transcriptional activation in response to WNT signaling. In conjunction with NF-kappaB, beta-catenin enhanced expression of immunosuppressive interleukin-10 and suppressed antitumoral CCL3, indicating that beta-catenin can induce a favorable tumor microenvironment. Thus, parallel activation of NF-kappaB and beta-catenin signaling by gain-of-function mutations in CARMA1 augments WNT stimulation and is required for regulating the expression of distinct NF-kappaB target genes to trigger cell-intrinsic and extrinsic processes that promote DLBCL lymphomagenesis.
    Type of Publication: Journal article published
    PubMed ID: 26776161
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  • 2
    Abstract: Purpose: Programmed death ligand-1 (PD-L1), encoded by the CD274 gene, is a target for immune checkpoint blockade; however, little is known about genomic CD274 alterations. A subset of small-cell lung cancer (SCLC) exhibits increased copy number of chromosome 9p24, on which CD274 resides; however, most SCLCs show low expression of PD-L1. We therefore examined whether CD274 is a target of recurrent genomic alterations.Experimental Design: We examined somatic copy number alterations in two patient cohorts by quantitative real-time PCR in 72 human SCLC cases (cohort 1) and SNP array analysis in 138 human SCLC cases (cohort 2). Whole-genome sequencing revealed the detailed genomic structure underlying focal amplification. PD-L1 expression in amplified cases from cohorts 1 and 2 was further examined by transcriptome sequencing and immunohistochemical (IHC) staining.Results: By examining somatic copy number alterations in two cohorts of primary human SCLC specimens, we observed 9p24 copy number gains (where CD274 resides) and focal, high-level amplification of CD274 We found evidence for genomic targeting of CD274, suggesting selection during oncogenic transformation. CD274 amplification was caused by genomic rearrangements not affecting the open reading frame, thus leading to massively increased CD274 transcripts and high level expression of PD-L1.Conclusions: A subset (4/210, 1.9%) of human SCLC patient cases exhibits massive expression of PD-L1 caused by focal amplification of CD274 Such tumors may be particularly susceptible to immune checkpoint blockade. Clin Cancer Res; 23(5); 1220-6. (c)2016 AACR.
    Type of Publication: Journal article published
    PubMed ID: 27620277
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  • 3
    Abstract: Oncogenic fusion events have been identified in a broad range of tumors. Among them, RET rearrangements represent distinct and potentially druggable targets that are recurrently found in lung adenocarcinomas. We provide further evidence that current anti-RET drugs may not be potent enough to induce durable responses in such tumors. We report that potent inhibitors, such as AD80 or ponatinib, that stably bind in the DFG-out conformation of RET may overcome these limitations and selectively kill RET-rearranged tumors. Using chemical genomics in conjunction with phosphoproteomic analyses in RET-rearranged cells, we identify the CCDC6-RETI788N mutation and drug-induced mitogen-activated protein kinase pathway reactivation as possible mechanisms by which tumors may escape the activity of RET inhibitors. Our data provide mechanistic insight into the druggability of RET kinase fusions that may be of help for the development of effective therapies targeting such tumors.
    Type of Publication: Journal article published
    PubMed ID: 28615362
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  • 4
    Abstract: The adaptor protein MYD88 is critical for relaying activation of Toll-like receptor signaling to NF-kappaB activation. MYD88 mutations, particularly the p.L265P mutation, have been described in numerous distinct B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL). Twenty-nine percent of activated B-cell-type DLBCL (ABC-DLBCL), which is characterized by constitutive activation of the NF-kappaB pathway, carry the p.L265P mutation. In addition, ABC-DLBCL frequently displays focal copy number gains affecting BCL2 Here, we generated a novel mouse model in which Cre-mediated recombination, specifically in B cells, leads to the conditional expression of Myd88(p.L252P) (the orthologous position of the human MYD88(p.L265P) mutation) from the endogenous locus. These mice develop a lymphoproliferative disease and occasional transformation into clonal lymphomas. The clonal disease displays the morphologic and immunophenotypical characteristics of ABC-DLBCL. Lymphomagenesis can be accelerated by crossing in a further novel allele, which mediates conditional overexpression of BCL2 Cross-validation experiments in human DLBCL samples revealed that both MYD88 and CD79B mutations are substantially enriched in ABC-DLBCL compared with germinal center B-cell DLBCL. Furthermore, analyses of human DLBCL genome sequencing data confirmed that BCL2 amplifications frequently co-occurred with MYD88 mutations, further validating our approach. Finally, in silico experiments revealed that MYD88-mutant ABC-DLBCL cells in particular display an actionable addiction to BCL2. Altogether, we generated a novel autochthonous mouse model of ABC-DLBCL that could be used as a preclinical platform for the development and validation of novel therapeutic approaches for the treatment of ABC-DLBCL.
    Type of Publication: Journal article published
    PubMed ID: 27048211
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  • 5
    Keywords: albumin, apheresis, BIOPSIES, BIOPSY, BLOOD, cryoglobulinemia, CRYOGLOBULINEMIC GLOMERULONEPHRITIS,
    Abstract: A 38-year-old pregnant woman (19th week of pregnancy) complained of fatigue, cold inducible paresthesias, generalized edema and mild arterial hypertension. Her past medical history was notable for frequent episodes of polyarthralgia and positivity for rheumatoid factor. On admission, acanthocyturia and unselective glomerular-tubular proteinuria with 19 g/d were detected with a slight decrease in creatinine clearance. Rheumatoid factor was robustly elevated and a cryocrit of 1.5 vol%, caused by a so far unknown replicative hepatitis C, was detected. Renal biopsy yielded membrano-proliferative glomerulonephritis. During pregnancy, high-dose corticosteroid therapy was administered. Edema disappeared and blood pressure normalized under albumin substitution and low-dose furosemide application. However, Cesarian section became necessary due to placental insufficiency at 27 weeks of gestation. Thereafter, neither virus load, cryocrit nor proteinuria decreased significantly under a combined therapy with pegylated interferon-a and ribavirin. Thus, cryoprecipitate apheresis was initiated resulting in robust decreases of clinical complaints, viral load, cryocrit and proteinuria. Cryoglobulinemia with renal involvement caused by hepatitis C is difficult to treat due to limitations of immunosuppressive and anti-viral therapy. In our patient, cryoprecipitate apheresis was a safe and effective therapeutic addition to standard therapy
    Type of Publication: Journal article published
    PubMed ID: 17474561
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  • 6
    Keywords: EXPRESSION ; IN-VITRO ; tumor ; Germany ; IN-VIVO ; VITRO ; VIVO ; CLASSIFICATION ; SYSTEM ; liver ; RISK ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; transcription ; DNA ; MECHANISM ; RISK-FACTORS ; RAT ; hepatocytes ; mechanisms ; treatment ; hormone ; RAT-LIVER ; gene expression ; DNA microarray ; microarrays ; PROMOTER ; risk factors ; CARCINOGENS ; MICROARRAY ANALYSIS ; PEROXISOME PROLIFERATOR ; dehydroepiandrosterone ; CLUSTER ; RE ; CLUSTER-ANALYSIS ; FEMALE RATS ; ENZYME ; cluster analysis ; PROFILES ; TECHNOLOGY ; DNA MICROARRAYS ; TOXICOGENOMICS ; RISK-FACTOR ; in vivo ; SHORT-TERM ; ALPHA-HEXACHLOROCYCLOHEXANE ; HEXACHLOROCYCLOHEXANE ISOMERS ; in vitro assay ; IN-VITRO INDUCTION ; NONGENOTOXIC CARCINOGENS ; rat liver slices ; RNA EXPRESSION ; TAT-BINDING PROTEIN-1 ; tumor promoters
    Abstract: Transcription profiling is used as an in vivo method for predicting the mode-of-action class of nongenotoxic carcinogens. To set up a reliable in vitro short-term test system DNA microarray technology was combined with rat liver slices. Seven compounds known to act as tumor promoters were selected, which included the enzyme inducers phenobarbital, alpha-hexachlorocyclohexane, and cyproterone acetate; the peroxisome proliferators WY-14,643, dehydroepiandrosterone, and ciprofibrate; and the hormone 17 alpha-ethinylestradiol. Rat liver slices were exposed to various concentrations of the compounds for 24 h. Toxicology-focused TOXaminer (TM) DNA microarrays containing approximately 1500 genes were used for generating gene expression profiles for each of the test compound. Hierarchical cluster analysis revealed that (i) gene expression profiles generated in rat liver slices in vitro were specific allowing classification of compounds with similar mode of action and (ii) expression profiles of rat liver slices exposed in vitro correlate with those induced after in vivo treatment (reported previously). Enzyme inducers and peroxisome proliferators formed two separate clusters, confirming that they act through different mechanisms. Expression profiles of the hormone 17 alpha-ethinylestradiol were not similar to any of the other compounds. In conclusion, gene expression profiles induced by compounds that act via similar mechanisms showed common effects on transcription upon treatment in vivo and in rat liver slices in vitro
    Type of Publication: Journal article published
    PubMed ID: 16940010
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