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  • 1
    Keywords: GENOME ; transcription ; DNA ; BINDING ; AMPLIFICATION ; C-MYC ; EMBRYONIC STEM-CELLS ; CAD PROMOTER ; RNA GENES ; MIZ-1
    Abstract: In mammalian cells, the MYC oncoprotein binds to thousands of promoters. During mitogenic stimulation of primary lymphocytes, MYC promotes an increase in the expression of virtually all genes. In contrast, MYC-driven tumour cells differ from normal cells in the expression of specific sets of up- and downregulated genes that have considerable prognostic value. To understand this discrepancy, we studied the consequences of inducible expression and depletion of MYC in human cells and murine tumour models. Changes in MYC levels activate and repress specific sets of direct target genes that are characteristic of MYC-transformed tumour cells. Three factors account for this specificity. First, the magnitude of response parallels the change in occupancy by MYC at each promoter. Functionally distinct classes of target genes differ in the E-box sequence bound by MYC, suggesting that different cellular responses to physiological and oncogenic MYC levels are controlled by promoter affinity. Second, MYC both positively and negatively affects transcription initiation independent of its effect on transcriptional elongation. Third, complex formation with MIZ1 (also known as ZBTB17) mediates repression of multiple target genes by MYC and the ratio of MYC and MIZ1 bound to each promoter correlates with the direction of response.
    Type of Publication: Journal article published
    PubMed ID: 25043018
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  • 2
    Keywords: CANCER ; IFN-GAMMA ; vaccination ; STEM-CELL TRANSPLANTATION ; COMPLETE REMISSION ; MULTIPLE-MYELOMA ; MYELODYSPLASTIC SYNDROME ; CYTOTOXIC T-LYMPHOCYTES ; WT1 PEPTIDE ; TUMOR REJECTION
    Abstract: Identification of physiologically relevant peptide vaccine targets calls for the direct analysis of the entirety of naturally presented human leukocyte antigen (HLA) ligands, termed the HLA ligandome. In this study, we implemented this direct approach using immunoprecipitation and mass spectrometry to define acute myeloid leukemia (AML)-associated peptide vaccine targets. Mapping the HLA class I ligandomes of 15 AML patients and 35 healthy controls, more than 25 000 different naturally presented HLA ligands were identified. Target prioritization based on AML exclusivity and high presentation frequency in the AML cohort identified a panel of 132 LiTAAs (ligandome-derived tumor-associated antigens), and 341 corresponding HLA ligands (LiTAPs (ligandome-derived tumor-associated peptides)) represented subset independently in 〉20% of AML patients. Functional characterization of LiTAPs by interferon-gamma ELISPOT (Enzyme-Linked ImmunoSpot) and intracellular cytokine staining confirmed AML-specific CD8(+) T-cell recognition. Of note, our platform identified HLA ligands representing several established AML-associated antigens (e.g. NPM1, MAGED1, PRTN3, MPO, WT1), but found 80% of them to be also represented in healthy control samples. Mapping of HLA class II ligandomes provided additional CD4(+) T-cell epitopes and potentially synergistic embedded HLA ligands, allowing for complementation of a multipeptide vaccine for the immunotherapy of AML.
    Type of Publication: Journal article published
    PubMed ID: 25092142
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  • 3
    Abstract: Direct analysis of HLA-presented antigens by mass spectrometry provides a comprehensive view on the antigenic landscape of different tissues/malignancies and enables the identification of novel, pathophysiologically relevant T-cell epitopes. Here, we present a systematic and comparative study of the HLA class I and II presented, nonmutant antigenome of multiple myeloma (MM). Quantification of HLA surface expression revealed elevated HLA molecule counts on malignant plasma cells compared with normal B cells, excluding relevant HLA downregulation in MM. Analyzing the presentation of established myeloma-associated T-cell antigens on the HLA ligandome level, we found a substantial proportion of antigens to be only infrequently presented on primary myelomas or to display suboptimal degrees of myeloma specificity. However, unsupervised analysis of our extensive HLA ligand data set delineated a panel of 58 highly specific myeloma-associated antigens (including multiple myeloma SET domain containing protein) which are characterized by frequent and exclusive presentation on myeloma samples. Functional characterization of these target antigens revealed peptide-specific, preexisting CD8(+) T-cell responses exclusively in myeloma patients, which is indicative of pathophysiological relevance. Furthermore, in vitro priming experiments revealed that peptide-specific T-cell responses can be induced in response-naive myeloma patients. Together, our results serve to guide antigen selection for T-cell-based immunotherapy of MM.
    Type of Publication: Journal article published
    PubMed ID: 26138685
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  • 4
    Abstract: Four distinct subgroups of cerebellar medulloblastomas (MBs) differ in their histopathology, molecular profiles, and prognosis. c-Myc (Myc) or MycN overexpression in granule neuron progenitors (GNPs) induces Group 3 (G3) or Sonic Hedgehog (SHH) MBs, respectively. Differences in Myc and MycN transcriptional profiles depend, in part, on their interaction with Miz1, which binds strongly to Myc but not MycN, to target sites on chromatin. Myc suppresses ciliogenesis and reprograms the transcriptome of SHH-dependent GNPs through Miz1-dependent gene repression to maintain stemness. Genetic disruption of the Myc/Miz1 interaction inhibited G3 MB development. Target genes of Myc/Miz1 are repressed in human G3 MBs but not in other subgroups. Therefore, the Myc/Miz1 interaction is a defining hallmark of G3 MB development.
    Type of Publication: Journal article published
    PubMed ID: 26766587
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  • 5
    Abstract: Recent studies suggest that multiple myeloma is an immunogenic disease, which might be effectively targeted by antigen-specific T-cell immunotherapy. As standard of care in myeloma includes proteasome inhibitor therapy, it is of great importance to characterize the effects of this treatment on HLA-restricted antigen presentation and implement only robustly presented targets for immunotherapeutic intervention. Here, we present a study that longitudinally and semi-quantitatively maps the effects of the proteasome inhibitor carfilzomib on HLA-restricted antigen presentation. The relative presentation levels of 4780 different HLA ligands were quantified in an in vitro model employing carfilzomib treatment of MM.1S and U266 myeloma cells, which revealed significant modulation of a substantial fraction of the HLA-presented peptidome. Strikingly, we detected selective down-modulation of HLA ligands with aromatic C-terminal anchor amino acids. This particularly manifested as a marked reduction in the presentation of HLA ligands through the HLA allotypes A*23:01 and A*24:02 on MM.1S cells. These findings implicate that carfilzomib mediates a direct, peptide motif-specific inhibitory effect on HLA ligand processing and presentation. As a substantial proportion of HLA allotypes present peptides with aromatic C-termini, our results may have broad implications for the implementation of antigen-specific treatment approaches in patients undergoing carfilzomib treatment.
    Type of Publication: Journal article published
    PubMed ID: 27058226
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  • 6
    Abstract: Hematological malignancies (HM) are highly amenable targets for immunotherapeutic intervention and may be effectively treated by antigen-specific T-cell based treatment. Recent studies demonstrate that physiologically occurring anti-cancer T-cell responses in certain HM entities target broadly presented non-mutated epitopes. HLA ligands are thus implied as prime targets for broadly applicable and antigen-specific off-the-shelf compounds. With the aim of assessing the presence of common targets shared among different HM which may enable addressing a larger patient collective we conducted a meta-analysis of 83 mass spectrometry-based HLA peptidome datasets (comprising 40,361 unique peptide identifications) across four major HM (19 AML, 16 CML, 35 CLL, and 13 MM/MCL samples) and investigated similarities and differences within the HLA presented antigenic landscape. We found the cancer HLA peptidome datasets to cluster specifically along entity and lineage lines, suggesting that the immunopeptidome directly reflects the differences in the underlying (tumor-)biology. In line with these findings, we only detected a small set of entity-spanning antigens, which were predominantly characterized by low presentation frequencies within the different patient cohorts. These findings suggest that design of T-cell immunotherapies for the treatment of HM should ideally be conducted in an entity-specific fashion.
    Type of Publication: Journal article published
    PubMed ID: 28159928
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  • 7
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    German Medical Science; Düsseldorf, Köln
    In:  122. Kongress der Deutschen Gesellschaft für Chirurgie; 20050405-20050408; München; DOC05dgch3642 /20050615/
    Publication Date: 2005-06-16
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 8
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Journal of Organometallic Chemistry 134 (1977), S. C37-C39 
    ISSN: 0022-328X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 9
    Publication Date: 2014-07-22
    Description: In mammalian cells, the MYC oncoprotein binds to thousands of promoters. During mitogenic stimulation of primary lymphocytes, MYC promotes an increase in the expression of virtually all genes. In contrast, MYC-driven tumour cells differ from normal cells in the expression of specific sets of up- and downregulated genes that have considerable prognostic value. To understand this discrepancy, we studied the consequences of inducible expression and depletion of MYC in human cells and murine tumour models. Changes in MYC levels activate and repress specific sets of direct target genes that are characteristic of MYC-transformed tumour cells. Three factors account for this specificity. First, the magnitude of response parallels the change in occupancy by MYC at each promoter. Functionally distinct classes of target genes differ in the E-box sequence bound by MYC, suggesting that different cellular responses to physiological and oncogenic MYC levels are controlled by promoter affinity. Second, MYC both positively and negatively affects transcription initiation independent of its effect on transcriptional elongation. Third, complex formation with MIZ1 (also known as ZBTB17) mediates repression of multiple target genes by MYC and the ratio of MYC and MIZ1 bound to each promoter correlates with the direction of response.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Walz, Susanne -- Lorenzin, Francesca -- Morton, Jennifer -- Wiese, Katrin E -- von Eyss, Bjorn -- Herold, Steffi -- Rycak, Lukas -- Dumay-Odelot, Helene -- Karim, Saadia -- Bartkuhn, Marek -- Roels, Frederik -- Wustefeld, Torsten -- Fischer, Matthias -- Teichmann, Martin -- Zender, Lars -- Wei, Chia-Lin -- Sansom, Owen -- Wolf, Elmar -- Eilers, Martin -- England -- Nature. 2014 Jul 24;511(7510):483-7. doi: 10.1038/nature13473. Epub 2014 Jul 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Theodor Boveri Institute, Biocenter, University of Wurzburg, Am Hubland, 97074 Wurzburg, Germany [2]. ; CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK. ; Theodor Boveri Institute, Biocenter, University of Wurzburg, Am Hubland, 97074 Wurzburg, Germany. ; Institute for Molecular Biology and Tumor Research (IMT), Emil-Mannkopff-Str.2, 35033 Marburg, Germany. ; University of Bordeaux, IECB, ARNA laboratory, Equipe Labellisee Contre le Cancer, 33600 Pessac, France. ; Institute for Genetics, Justus-Liebig-University, Heinrich-Buff-Ring 58, 35390 Giessen, Germany. ; University Children's Hospital of Cologne, and Cologne Center for Molecular Medicine (CMMC), University of Cologne, Kerpener Str. 62, 50924 Cologne, Germany. ; University Hospital Tubingen, Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, Otfried-Mueller-Strasse 10, 72076 Tubingen, Germany. ; 1] University Hospital Tubingen, Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, Otfried-Mueller-Strasse 10, 72076 Tubingen, Germany [2] Translational Gastrointestinal Oncology Group within the German Center for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany. ; DOE Joint Genome Institute, 2800 Mitchell Drive, Walnut Creek, California 94598, USA. ; 1] Theodor Boveri Institute, Biocenter, University of Wurzburg, Am Hubland, 97074 Wurzburg, Germany [2] Rudolf Virchow Center/DFG Research Center for Experimental Biomedicine, University of Wurzburg, Josef-Schneider-Str.2, 97080 Wurzburg, Germany [3]. ; 1] Theodor Boveri Institute, Biocenter, University of Wurzburg, Am Hubland, 97074 Wurzburg, Germany [2] Comprehensive Cancer Center Mainfranken, University of Wurzburg, Josef-Schneider-Str. 6, 97080 Wurzburg, Germany [3].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043018" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Cell Line, Tumor ; Down-Regulation/*genetics ; E-Box Elements/genetics ; Gene Expression Regulation, Neoplastic/*genetics ; Genes, myc/*genetics ; Humans ; Kruppel-Like Transcription Factors/metabolism ; Mice ; Neoplasms/*genetics ; Nuclear Proteins/metabolism ; Promoter Regions, Genetic/genetics ; Protein Inhibitors of Activated STAT/metabolism ; Proto-Oncogene Proteins c-myc/genetics/metabolism ; RNA Polymerase II/metabolism ; *Transcriptome ; Up-Regulation/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2016-03-12
    Description: The MYC oncogene codes for a transcription factor that is overexpressed in many human cancers. Here we show that MYC regulates the expression of two immune checkpoint proteins on the tumor cell surface: the innate immune regulator CD47 (cluster of differentiation 47) and the adaptive immune checkpoint PD-L1 (programmed death-ligand 1). Suppression of MYC in mouse tumors and human tumor cells caused a reduction in the levels of CD47 and PD-L1 messenger RNA and protein. MYC was found to bind directly to the promoters of the Cd47 and Pd-l1 genes. MYC inactivation in mouse tumors down-regulated CD47 and PD-L1 expression and enhanced the antitumor immune response. In contrast, when MYC was inactivated in tumors with enforced expression of CD47 or PD-L1, the immune response was suppressed, and tumors continued to grow. Thus, MYC appears to initiate and maintain tumorigenesis, in part, through the modulation of immune regulatory molecules.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Casey, Stephanie C -- Tong, Ling -- Li, Yulin -- Do, Rachel -- Walz, Susanne -- Fitzgerald, Kelly N -- Gouw, Arvin M -- Baylot, Virginie -- Gutgemann, Ines -- Eilers, Martin -- Felsher, Dean W -- 1F32CA177139/CA/NCI NIH HHS/ -- 5T32AI07290/AI/NIAID NIH HHS/ -- CA 089305/CA/NCI NIH HHS/ -- CA 170378/CA/NCI NIH HHS/ -- CA 184384/CA/NCI NIH HHS/ -- U01 CA 114747/CA/NCI NIH HHS/ -- U01 CA 188383/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2016 Apr 8;352(6282):227-31. doi: 10.1126/science.aac9935. Epub 2016 Mar 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. ; Comprehensive Cancer Center Mainfranken, Core Unit Bioinformatics, Biocenter, University of Wurzburg, Am Hubland, 97074 Wurzburg, Germany. ; Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany. ; Comprehensive Cancer Center Mainfranken, Core Unit Bioinformatics, Biocenter, University of Wurzburg, Am Hubland, 97074 Wurzburg, Germany. Theodor Boveri Institute, Biocenter, University of Wurzburg, Am Hubland, 97074 Wurzburg, Germany. ; Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. dfelsher@stanford.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26966191" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD274/*genetics ; Antigens, CD47/*genetics ; Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics/*immunology ; Down-Regulation ; *Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Humans ; Immune Tolerance/*genetics ; Jurkat Cells ; Lymphoma/genetics/immunology ; Mice ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics/immunology ; Promoter Regions, Genetic ; Proto-Oncogene Proteins c-myc/genetics/*metabolism ; RNA, Small Interfering/genetics
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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