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1. Transcriptional reprogramming by mutated IRF4 in lymphoma

Author

Schleussner, Nikolai, Cauchy, Pierre, Franke, Vedran, Giefing, Maciej, Fornes, Oriol, Vankadari, Naveen, Assi, Salam A., Costanza, Mariantonia, Weniger, Marc A., Akalin, Altuna, Anagnostopoulos, Ioannis, Bukur, Thomas, Casarotto, Marco G., Damm, Frederik, Daumke, Oliver, Edginton-White, Benjamin, Gebhardt, J. Christof M., Grau, Michael, Grunwald, Stephan, Hansmann, Martin-Leo, Hartmann, Sylvia, Huber, Lionel, Kärgel, Eva, Lusatis, Simone, Noerenberg, Daniel, Obier, Nadine, Pannicke, Ulrich, Fischer, Anja, Reisser, Anja, Rosenwald, Andreas, Schwarz, Klaus, Sundararaj, Srinivasan, Weilemann, Andre, Winkler, Wiebke, Xu, Wendan, Lenz, Georg, Rajewsky, Klaus, Wasserman, Wyeth W., Cockerill, Peter N., Scheidereit, Claus, Siebert, Reiner, Küppers, Ralf, Grosschedl, Rudolf, Janz, Martin, Bonifer, Constanze, and Mathas, Stephan

Published
2023
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2. The genomic and transcriptional landscape of primary central nervous system lymphoma

Author

Radke, Josefine, Ishaque, Naveed, Koll, Randi, Gu, Zuguang, Schumann, Elisa, Sieverling, Lina, Uhrig, Sebastian, Hübschmann, Daniel, Toprak, Umut H., López, Cristina, Hostench, Xavier Pastor, Borgoni, Simone, Juraeva, Dilafruz, Pritsch, Fabienne, Paramasivam, Nagarajan, Balasubramanian, Gnana Prakash, Schlesner, Matthias, Sahay, Shashwat, Weniger, Marc, Pehl, Debora, Radbruch, Helena, Osterloh, Anja, Korfel, Agnieszka, Misch, Martin, Onken, Julia, Faust, Katharina, Vajkoczy, Peter, Moskopp, Dag, Wang, Yawen, Jödicke, Andreas, Trümper, Lorenz, Anagnostopoulos, Ioannis, Lenze, Dido, Küppers, Ralf, Hummel, Michael, Schmitt, Clemens A., Wiestler, Otmar D., Wolf, Stephan, Unterberg, Andreas, Eils, Roland, Herold-Mende, Christel, Brors, Benedikt, Siebert, Reiner, Wiemann, Stefan, and Heppner, Frank L.

Published
2022
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4. Mutational mechanisms shaping the coding and noncoding genome of germinal center derived B-cell lymphomas

Author

Hübschmann, Daniel, Kleinheinz, Kortine, Wagener, Rabea, Bernhart, Stephan H., López, Cristina, Toprak, Umut H., Sungalee, Stephanie, Ishaque, Naveed, Kretzmer, Helene, Kreuz, Markus, Waszak, Sebastian M., Paramasivam, Nagarajan, Ammerpohl, Ole, Aukema, Sietse M., Beekman, Renée, Bergmann, Anke K., Bieg, Matthias, Binder, Hans, Borkhardt, Arndt, Borst, Christoph, Brors, Benedikt, Bruns, Philipp, Carrillo de Santa Pau, Enrique, Claviez, Alexander, Doose, Gero, Haake, Andrea, Karsch, Dennis, Haas, Siegfried, Hansmann, Martin-Leo, Hoell, Jessica I., Hovestadt, Volker, Huang, Bingding, Hummel, Michael, Jäger-Schmidt, Christina, Kerssemakers, Jules N. A., Korbel, Jan O., Kube, Dieter, Lawerenz, Chris, Lenze, Dido, Martens, Joost H. A., Ott, German, Radlwimmer, Bernhard, Reisinger, Eva, Richter, Julia, Rico, Daniel, Rosenstiel, Philip, Rosenwald, Andreas, Schillhabel, Markus, Stilgenbauer, Stephan, Stadler, Peter F., Martín-Subero, José I., Szczepanowski, Monika, Warsow, Gregor, Weniger, Marc A., Zapatka, Marc, Valencia, Alfonso, Stunnenberg, Hendrik G., Lichter, Peter, Möller, Peter, Loeffler, Markus, Eils, Roland, Klapper, Wolfram, Hoffmann, Steve, Trümper, Lorenz, Küppers, Ralf, Schlesner, Matthias, and Siebert, Reiner

Published
2021
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6. Lymphocyte predominant cells detect Moraxella catarrhalis-derived antigens in nodular lymphocyte-predominant Hodgkin lymphoma

Author

Thurner, Lorenz, Hartmann, Sylvia, Fadle, Natalie, Regitz, Evi, Kemele, Maria, Kim, Yoo-Jin, Bohle, Rainer Maria, Nimmesgern, Anna, von Müller, Lutz, Kempf, Volkhard A. J., Weniger, Marc A., Neumann, Frank, Schneider, Nadine, Vornanen, Martine, Sundström, Christer, de Leval, Laurence, Engert, Andreas, Eichenauer, Dennis A., Küppers, Ralf, Preuss, Klaus-Dieter, Hansmann, Martin-Leo, and Pfreundschuh, Michael

Published
2020
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7. Methylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL

Author

Wierzbinska, Justyna A., Toth, Reka, Ishaque, Naveed, Rippe, Karsten, Mallm, Jan-Philipp, Klett, Lara C., Mertens, Daniel, Zenz, Thorsten, Hielscher, Thomas, Seifert, Marc, Küppers, Ralf, Assenov, Yassen, Lutsik, Pavlo, Stilgenbauer, Stephan, Roessner, Philipp M., Seiffert, Martina, Byrd, John, Oakes, Christopher C., Plass, Christoph, and Lipka, Daniel B.

Published
2020
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8. Human IgM–expressing memory B cells.

Author

Budeus, Bettina, Kibler, Artur, and Küppers, Ralf

Subjects
IMMUNOLOGIC memory, B cells, ANTIGEN receptors, GERMINAL centers, T cells
Abstract

A hallmark of T cell dependent (TD) humoral immune responses is the generation of long–lived memory B cells. The generation of these cells occurs primarily in the germinal center (GC) reaction, where antigen–activated B cells undergo affinity maturation as a major consequence of the combined processes of proliferation, somatic hypermutation of their immunoglobulin V (IgV) region genes, and selection for improved affinity of their B–cell antigen receptors. As many B cells also undergo class–switching to IgG or IgA in these TD responses, there was traditionally a focus on class–switched memory B cells in both murine and human studies on memory B cells. However, it has become clear that there is also a large subset of IgM–expressing memory B cells, which have important phenotypic and functional similarities but also differences to class–switched memory B cells. There is an ongoing discussion about the origin of distinct subsets of human IgM+ B cells with somatically mutated IgV genes. We argue here that the vast majority of human IgM–expressing B cells with somatically mutated IgV genes in adults is indeed derived from GC reactions, even though a generation of some mostly lowly mutated IgM+ B cells from other differentiation pathways, mainly in early life, may exist. [ABSTRACT FROM AUTHOR]

Published
2023
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12. Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma

Author

López, Cristina, Kleinheinz, Kortine, Aukema, Sietse M., Rohde, Marius, Bernhart, Stephan H., Hübschmann, Daniel, Wagener, Rabea, Toprak, Umut H., Raimondi, Francesco, Kreuz, Markus, Waszak, Sebastian M., Huang, Zhiqin, Sieverling, Lina, Paramasivam, Nagarajan, Seufert, Julian, Sungalee, Stephanie, Russell, Robert B., Bausinger, Julia, Kretzmer, Helene, Ammerpohl, Ole, Bergmann, Anke K., Binder, Hans, Borkhardt, Arndt, Brors, Benedikt, Claviez, Alexander, Doose, Gero, Feuerbach, Lars, Haake, Andrea, Hansmann, Martin-Leo, Hoell, Jessica, Hummel, Michael, Korbel, Jan O., Lawerenz, Chris, Lenze, Dido, Radlwimmer, Bernhard, Richter, Julia, Rosenstiel, Philip, Rosenwald, Andreas, Schilhabel, Markus B., Stein, Harald, Stilgenbauer, Stephan, Stadler, Peter F., Szczepanowski, Monika, Weniger, Marc A., Zapatka, Marc, Eils, Roland, Lichter, Peter, Loeffler, Markus, Möller, Peter, Trümper, Lorenz, Klapper, Wolfram, ICGC MMML-Seq Consortium, Hoffmann, Steve, Küppers, Ralf, Burkhardt, Birgit, Schlesner, Matthias, and Siebert, Reiner

Published
2019
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13. Clonal composition and differentiation stage of human CD30+ B cells in reactive lymph nodes.

Author

Küppers, Ralf, Budeus, Bettina, Hartmann, Sylvia, and Hansmann, Martin-Leo

Subjects
B cells, B cell differentiation, LYMPH nodes, LYMPHADENITIS, HODGKIN'S disease
Abstract

Introduction: Normal CD30+ B cells represent a distinct B-cell differentiation stage with features of strong activation. We lack an in depth understanding of these cells, because they are not present in peripheral blood and are typically very rare in reactive lymphoid organs. CD30+ B cells have been discussed as a potential precursor population for the malignant CD30+ Hodgkin and Reed-Sternberg cells in classical Hodgkin lymphoma. As CD30+ B cells can be more numerous in some cases of reactive lymphadenitis, we aimed to characterize these CD30+ B cells in terms of their differentiation stage and clonal composition, also as a means to clarify whether such CD30+ B-cell populations may represent potential precursor lesions of Hodgkin lymphoma. Methods: We microdissected single CD30+ B cells from tissue sections of eight reactive lymph nodes with substantial numbers of such cells and sequenced their rearranged immunoglobulin (Ig) heavy chain V region (IGHV) genes. Results: The CD30+ B cells were polyclonal B cells in all instances, and they not only encompass post-germinal center (GC) B cells with mutated IGHV genes, but also include a substantial fraction of pre-germinal center B cells with unmutated IGHV genes. In five of the lymph nodes, mostly small clonal expansions were detected among the CD30+ B cells. Most of the expanded clones carried somatically mutated IGHV genes and about half of the mutated clones showed intraclonal diversity. Discussion: We conclude that in human reactive lymph nodes with relatively many CD30+ B cells, these cells are a heterogenous population of polyclonal B cells encompassing activated pre-GC B cells as well as GC and post-GC B cells, with some clonal expansions. Because of their polyclonality and frequent pre-GC differentiation stage, there is no indication that such cell-rich CD30+ B-cell populations represent precursor lesions of Hodgkin lymphoma. [ABSTRACT FROM AUTHOR]

Published
2023
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24. Distinct Chemokine Receptor Expression Profiles in De Novo DLBCL, Transformed Follicular Lymphoma, Richter's Trans-Formed DLBCL and Germinal Center B-Cells.

Author

Uhl, Barbara, Prochazka, Katharina T., Pansy, Katrin, Wenzl, Kerstin, Strobl, Johanna, Baumgartner, Claudia, Szmyra, Marta M., Waha, James E., Wolf, Axel, Tomazic, Peter V., Steinbauer, Elisabeth, Steinwender, Maria, Friedl, Sabine, Weniger, Marc, Küppers, Ralf, Pichler, Martin, Greinix, Hildegard T., Stary, Georg, Ramsay, Alan G., and Apollonio, Benedetta

Subjects
FOLLICULAR lymphoma, CHEMOKINE receptors, DIFFUSE large B-cell lymphomas, GERMINAL centers, BIOMARKERS, RICHTER syndrome, RITUXIMAB, OVARIAN follicle
Abstract

Chemokine receptors and their ligands have been identified as playing an important role in the development of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and Richter syndrome (RS). Our aim was to investigate the different expression profiles in de novo DLBCL, transformed follicular lymphoma (tFL), and RS. Here, we profiled the mRNA expression levels of 18 chemokine receptors (CCR1–CCR9, CXCR1–CXCR7, CX3CR1 and XCR1) using RQ-PCR, as well as immunohistochemistry of seven chemokine receptors (CCR1, CCR4–CCR8 and CXCR2) in RS, de novo DLBCL, and tFL biopsy-derived tissues. Tonsil-derived germinal center B-cells (GC-B) served as non-neoplastic controls. The chemokine receptor expression profiles of de novo DLBCL and tFL substantially differed from those of GC-B, with at least 5-fold higher expression of 15 out of the 18 investigated chemokine receptors (CCR1–CCR9, CXCR1, CXCR2, CXCR6, CXCR7, CX3CR1 and XCR1) in these lymphoma subtypes. Interestingly, the de novo DLBCL and tFL exhibited at least 22-fold higher expression of CCR1, CCR5, CCR8, and CXCR6 compared with RS, whereas no significant difference in chemokine receptor expression profile was detected when comparing de novo DLBCL with tFL. Furthermore, in de novo DLBCL and tFLs, a high expression of CCR7 was associated with a poor overall survival in our study cohort, as well as in an independent patient cohort. Our data indicate that the chemokine receptor expression profile of RS differs substantially from that of de novo DLBCL and tFL. Thus, these multiple dysregulated chemokine receptors could represent novel clinical markers as diagnostic and prognostic tools. Moreover, this study highlights the relevance of chemokine signaling crosstalk in the tumor microenvironment of aggressive lymphomas. [ABSTRACT FROM AUTHOR]

Published
2022
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25. Loss of function mutations of BCOR in classical Hodgkin lymphoma.

Author

Giefing, Maciej, Gearhart, Micah D., Schneider, Markus, Overbeck, Birte, Klapper, Wolfram, Hartmann, Sylvia, Ustaszewski, Adam, Weniger, Marc A., Wiehle, Laura, Hansmann, Martin-Leo, Melnick, Ari, Béguelin, Wendy, Sundström, Christer, Küppers, Ralf, Bardwell, Vivian J., and Siebert, Reiner

Subjects
HODGKIN'S disease, REGULATOR genes, B cells, SOMATIC mutation, HEMATOLOGIC malignancies, GERMINAL centers
Abstract

BCOR is a component of a variant Polycomb repressive complex 1 (PRC1.1). PRC1 and PRC2 complexes together constitute a major gene regulatory system critical for appropriate cellular differentiation. The gene is upregulated in germinal center (GC) B cells and mutated in a number of hematologic malignancies. We report BCOR inactivating alterations in 4/7 classic Hodgkin lymphoma (cHL) cell lines, subclonal somatic mutations in Hodgkin and Reed–Sternberg (HRS) cells of 4/10 cHL cases, and deletions in HRS cells of 7/17 primary cHL cases. In mice, conditional loss of Bcor driven by AID-Cre in GC B cells resulted in gene expression changes of 46 genes (>2-fold) including upregulated Lef1 that encodes a transcription factor responsible for establishing T-cell identity and Il9r (interleukin-9 receptor), an important member of the cytokine network in cHL. Our findings suggest a role for BCOR loss in cHL pathogenesis and GC-B cell homeostasis. [ABSTRACT FROM AUTHOR]

Published
2022
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33. Publisher Correction: Epigenome-wide analysis of T-cell large granular lymphocytic leukemia identifies BCL11B as a potential biomarker.

Author

Johansson, Patricia, Laguna, Teresa, Ossowski, Julio, Pancaldi, Vera, Brauser, Martina, Dührsen, Ulrich, Keuneke, Lara, Queiros, Ana, Richter, Julia, Martín-Subero, José I., Siebert, Reiner, Schlegelberger, Brigitte, Küppers, Ralf, Dürig, Jan, Penas, Eva M. Murga, Pau, Enrique Carrillo-de Santa, and Bergmann, Anke K.

Published
2023
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35. High resolution SNP array genomic profiling of peripheral T cell lymphomas, not otherwise specified, identifies a subgroup with chromosomal aberrations affecting the REL locus

Author

Hartmann, Sylvia, Gesk, Stefan, Scholtysik, René, Kreuz, Markus, Bug, Stefanie, Vater, Inga, Döring, Claudia, Cogliatti, Sergio, Parrens, Marie, Merlio, Jean-Philippe, Kwiecinska, Anna, Porwit, Anna, Piccaluga, Pier Paolo, Pileri, Stefano, Hoefler, Gerald, Küppers, Ralf, Siebert, Reiner, and Hansmann, Martin-Leo

Published
2010
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38. The Splenic Marginal Zone in Children Is Characterized by a Subpopulation of CD27-Negative, Lowly IGHV-Mutated B Cells.

Author

Kibler, Artur, Budeus, Bettina, Küppers, Ralf, and Seifert, Marc

Subjects
B cells, BLOODBORNE infections, IMMUNOLOGIC memory, OLDER people
Abstract

Young children and older adults suffer from enhanced susceptibility to infections with blood-borne pathogens. An essential step towards immunity is the establishment of a splenic marginal zone (sMZ), which is immature at below 2 years of age. At approximately 5 years of age, an adult level of protection is reached but wanes again in older adults. Although the infant sMZ is thought to contain mostly naïve B cells, memory B cells are recruited to and recirculate from the sMZ throughout life, and class-switched sMZ B cells dominate in older adults. For a better resolution of naïve versus memory B-cell subset accumulation in the sMZ, we performed a single cell-based gene expression analysis of (CD21highIgMhigh) sMZ B cells among five healthy donors (age 3 to 48 years) and validated the sMZ B-cell subset composition by flow cytometry of 147 spleen biopsies (age 0 to 82 years). We identified a major sMZ B-cell subpopulation, which is abundant at birth but decreases with age. These cells lack CD27 expression but carry a weak-to-intermediate memory B-cell signature. These CD27neg sMZ B cells are either IGHV-unmutated or carry only a few IGHV mutations early in life but show average memory B-cell IGHV mutation frequencies (>3%) in adults. The activation and proliferation potential of CD27neg sMZ B cells is significantly above that of non-sMZ B cells already in children. Our study suggests that the human sMZ B-cell pool changes with age, encompassing a major population of lowly Ig-mutated CD27neg but antigen-experienced B cells early in life. [ABSTRACT FROM AUTHOR]

Published
2022
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39. PLK1‐dependent phosphorylation restrains EBNA2 activity and lymphomagenesis in EBV‐infected mice.

Author

Zhang, Xiang, Schuhmachers, Patrick, Mourão, André, Giansanti, Piero, Murer, Anita, Thumann, Sybille, Kuklik‐Roos, Cornelia, Beer, Sophie, Hauck, Stefanie M, Hammerschmidt, Wolfgang, Küppers, Ralf, Kuster, Bernhard, Raab, Monika, Strebhardt, Klaus, Sattler, Michael, Münz, Christian, and Kempkes, Bettina

Abstract

While Epstein–Barr virus (EBV) establishes a life‐long latent infection in apparently healthy human immunocompetent hosts, immunodeficient individuals are at particular risk to develop lymphoproliferative B‐cell malignancies caused by EBV. A key EBV protein is the transcription factor EBV nuclear antigen 2 (EBNA2), which initiates B‐cell proliferation. Here, we combine biochemical, cellular, and in vivo experiments demonstrating that the mitotic polo‐like kinase 1 (PLK1) binds to EBNA2, phosphorylates its transactivation domain, and thereby inhibits its biological activity. EBNA2 mutants that impair PLK1 binding or prevent EBNA2 phosphorylation are gain‐of‐function mutants. They exhibit enhanced transactivation capacities, accelerate the proliferation of infected B cells, and promote the development of monoclonal B‐cell lymphomas in infected mice. Thus, PLK1 coordinates the activity of EBNA2 to attenuate the risk of tumor incidences in favor of the establishment of latency in the infected but healthy host. SYNOPSIS: EBNA2 is a key transactivator that initiates B cell immortalization. PLK1 phosphorylates the C‐ terminal transactivation domain of EBNA2 to attenuate its oncogenic activities and promote the establishment of long term latency in the infected host. CDK1 phosphorylation of EBNA2 (S379) primes PLK1 binding via its polo box domain (PBD).The PLK1 kinase domain (KD) phosphorylates two residues in the EBNA2 transactivation domain (S457/T465).A second PLK1 binding region within the C‐terminus of EBNA2 confers weak CDK1 phosphorylation independent binding.Monoclonal B cell lymphomas more frequently arise in mice infected with EBV mutants expressing either EBNA2 (S379A) or EBNA2 (S457A/T465V) in comparison to EBV wild‐type infected mice. [ABSTRACT FROM AUTHOR]

Published
2021
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46. Transcriptional Profiling of the Nuclear Factor-κB Pathway Identifies a Subgroup of Primary Lymphoma of the Central Nervous System With Low BCL10 Expression

Author

Courts, Cornelius, Montesinos-Rongen, Manuel, Martin-Subero, Jose Ignacio, Brunn, Anna, Siemer, Dörte, Zühlke-Jenisch, Reina, Pels, Hendrik, Jürgens, Annika, Schlegel, Uwe, Schmidt-Wolf, Ingo G. H., Schaller, Carlo, Reifenberger, Guido, Sabel, Michael, Warnecke-Eberz, Ute, Wiestler, Otmar D., Küppers, Ralf, Siebert, Reiner, and Deckert, Martina

Published
2007
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