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Stefan Hartmann, Muna Brisam, Stephan Rauthe, Oliver Driemel, Roman C Brands, Andreas Rosenwald, Alexander C Kübler, Urs D A Müller-Richter
There is a growing body of evidence indicating that several melanoma-associated antigen-A (MAGE-A) subgroups contribute to the malignancy of head and neck cancer. The present study retrospectively analyzed the expression of all known MAGE-A subgroups in the tumor front and center of 38 head and neck cancer patients (Union for International Cancer Control stage I or IV) by immunohistochemistry. MAGE-A1, -A6, -A8, -A9 and -A11 were expressed at significantly higher levels at the tumor front of stage IV specimens compared with the tumor front of stage I specimens...
October 2016: Oncology Letters
E Müller, S Bauer, T Stühmer, A Mottok, C-J Scholz, T Steinbrunn, D Brünnert, A Brandl, H Schraud, S Kreßmann, A Beilhack, A Rosenwald, R C Bargou, M Chatterjee
Direct therapeutic targeting of oncogenic RAS is currently still impossible due to lack of suitable pharmacological inhibitors. Because specific blockade of druggable RAS effectors might represent an alternative treatment approach, we evaluated the role of the Raf complex for multiple myeloma (MM) pathobiology. We found frequent overexpression of the Raf isoforms (A-, B- and C-Raf) and downstream activation of MEK1,2/ERK1,2 in MM cells. Concomitant inhibition of all Raf isoforms (pan-Raf inhibition) by RNAi or pharmacological inhibitors was required to strongly induce apoptosis in MM cell lines, primary MM cells in vitro, and in a syngeneic MM mouse model in vivo...
September 30, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Larry Mansouri, Daniel Noerenberg, Emma Young, Elena Mylonas, Maysaa Abdulla, Mareike Frick, Fazila Asmar, Viktor Ljungström, Markus Schneider, Kenichi Yoshida, Aron Skaftason, Tatjana Pandzic, Blanca Gonzalez, Anna Tasidou, Nils Waldhueter, Alfredo Rivas-Delgado, Maria Angelopoulou, Marita Ziepert, Christopher Maximilian Arends, Lucile Couronné, Dido Lenze, Claudia D Baldus, Christian Bastard, Jessica Okosun, Jude Fitzgibbon, Bernd Dörken, Hans G Drexler, Damien Roos-Weil, Clemens A Schmitt, Helga Duverger Munch-Petersen, Thorsten Zenz, Martin-Leo Hansmann, Jonathan C Strefford, Gunilla Enblad, Olivier A Bernard, Elisabeth Ralfkiaer, Martin Erlanson, Penelope Korkolopoulou, Magnus Hultdin, Theodora Papadaki, Kirsten Grønbæk, Armando Lopez-Guillermo, Seishi Ogawa, Ralf Küppers, Kostas Stamatopoulos, Niki Stavroyianni, George Kanellis, Andreas Rosenwald, Elias Campo, Rose-Marie Amini, German Ott, Theodoros P Vassilakopoulos, Michael Hummel, Richard Rosenquist, Frederik Damm
We recently reported a truncating deletion in the NFKBIE gene, which encodes IκBϵ, a negative feedback regulator of NF-κB, in clinically aggressive chronic lymphocytic leukemia (CLL). Preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, hence we screened a large patient cohort (n=1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal-zone lymphoma, and T-cell acute lymphoblastic leukemia (<2%), slightly higher frequencies were seen in diffuse large B-cell lymphoma, mantle cell lymphoma, and primary CNS lymphoma (3-4%)...
September 26, 2016: Blood
Richard Rosenquist, Andreas Rosenwald, Ming-Qing Du, Gianluca Gaidano, Patricia Groenen, Andrew Wotherspoon, Paolo Ghia, Philippe Gaulard, Elias Campo, Kostas Stamatopoulos
Similar to the inherent clinical heterogeneity of most, if not all, lymphoma entities, the genetic landscape of these tumors is markedly complex in the majority of cases, with a rapidly growing list of recurrently mutated genes discovered in recent years by next-generation sequencing technology. Whilst a few genes have been implied to have diagnostic, prognostic and even predictive impact, most gene mutations still require rigorous validation in larger, preferably prospective patient series, to scrutinize their potential role in lymphoma diagnostics and patient management...
September 2016: Haematologica
S Rauthe, A Rosenwald
Lymphomas infiltrating the mediastinum are a challenge for the treating physician as well as for the pathological diagnostics. The clinical scenario is often an emergency situation, while the pathologist is usually confronted only with small biopsy samples. Classical Hodgkin's lymphoma is by far the most frequently occurring lymphoma in the mediastinum and predominantly the nodular sclerosis subtype. In small and very sclerotic specimens it can be difficult to morphologically detect Hodgkin and Reed-Sternberg cells and to identify the characteristic phenotype by immunohistochemistry...
September 2016: Der Pathologe
Shu Yang, Anne G Rosenwald
Macroautophagy/autophagy is a cellular degradation process that sequesters organelles or proteins into a double-membrane structure called the phagophore; this transient compartment matures into an autophagosome, which then fuses with the lysosome or vacuole to allow hydrolysis of the cargo. Factors that control membrane traffic are also essential for each step of autophagy. Here we demonstrate that 2 monomeric GTP-binding proteins in Saccharomyces cerevisiae, Arl1 and Ypt6, which belong to the Arf/Arl/Sar protein family and the Rab family, respectively, and control endosome-trans-Golgi traffic, are also necessary for starvation-induced autophagy under high temperature stress...
October 2, 2016: Autophagy
Anne G Rosenwald, Gaurav Arora, Rocco Ferrandino, Erica L Gerace, Maedeh Mohammednetej, Waseem Nosair, Shemona Rattila, Amanda Zirzow Subic, Ronda Rolfes
Candida glabrata is an important human fungal pathogen whose incidence continues to rise. Because many clinical isolates are resistant to azole drugs, the drugs of choice to treat such infections are members of the echinocandin family, although there are increasing reports of resistance to these drugs as well. In efforts to better understand the genetic changes that lead to altered responses to echinocandins, we screened a transposon-insertion library of mutants for strains to identify genes that are important for cellular responses to caspofungin, a member of this drug family...
2016: G3: Genes—Genomes—Genetics
Vindi Jurinovic, Robert Kridel, Annette M Staiger, Monika Szczepanowski, Heike Horn, Martin H Dreyling, Andreas Rosenwald, German Ott, Wolfram Klapper, Andrew D Zelenetz, Paul M Barr, Jonathan W Friedberg, Stephen Ansell, Laurie H Sehn, Joseph M Connors, Randy D Gascoyne, Wolfgang Hiddemann, Michael Unterhalt, David M Weinstock, Oliver Weigert
Follicular lymphoma (FL) is a clinically and molecularly heterogeneous disease. Posttreatment surrogate end points, such as progression of disease within 24 months (POD24) are promising predictors for overall survival (OS) but are of limited clinical value, primarily because they cannot guide up-front treatment decisions. We used the clinical and molecular data from 2 independent cohorts of symptomatic patients in need of first-line immunochemotherapy (151 patients from a German Low-Grade Lymphoma Study Group [GLSG] trial and 107 patients from a population-based registry of the British Columbia Cancer Agency [BCCA]) to validate the predictive utility of POD24, and to evaluate the ability of pretreatment risk models to predict early treatment failure...
August 25, 2016: Blood
Kebria Hezaveh, Andreas Kloetgen, Stephan H Bernhart, Kunal Das Mahapatra, Dido Lenze, Julia Richter, Andrea Haake, Anke K Bergmann, Benedikt Brors, Birgit Burkhardt, Alexander Claviez, Hans G Drexler, Roland Eils, Siegfried Haas, Steve Hoffmann, Dennis Karsch, Wolfram Klapper, Kortine Kleinheinz, Jan Korbel, Helene Kretzmer, Markus Kreuz, Ralf Küppers, Chris Lawerenz, Ellen Leich, Markus Loeffler, Luisa Mantovani-Loeffler, Cristina López, Alice C McHardy, Peter Möller, Marius Rohde, Philip Rosenstiel, Andreas Rosenwald, Markus Schilhabel, Matthias Schlesner, Ingrid Scholz, Peter F Stadler, Stephan Stilgenbauer, Séphanie Sungalee, Monika Szczepanowski, Lorenz Trümper, Marc A Weniger, Reiner Siebert, Arndt Borkhardt, Michael Hummel, Jessica I Hoell
MicroRNAs are well-established players in posttranscriptional gene regulation. However, information on the effects of microRNA deregulation mainly relies on bioinformatic prediction of potential targets, whereas proof of the direct physical microRNAs/target mRNAs interaction is mostly lacking. Within the International Cancer Genome Consortium Project Determining Molecular Mechanisms in Malignant Lymphoma by Sequencing (ICGC MMML-Seq), we performed miRnome sequencing from 16 Burkitt lymphomas, 19 diffuse large B-cell lymphomas, and 21 follicular lymphomas...
July 6, 2016: Haematologica
A Bouska, W Zhang, Q Gong, J Iqbal, A Scuto, J Vose, M Ludvigsen, K Fu, D D Weisenburger, T C Greiner, R D Gascoyne, A Rosenwald, G Ott, E Campo, L M Rimsza, J Delabie, E S Jaffe, R M Braziel, J M Connors, C-I Wu, L M Staudt, F D'Amore, T W McKeithan, W C Chan
Follicular lymphoma (FL) is typically an indolent disease, but 30-40% of FL cases transform into an aggressive lymphoma (tFL) with a poor prognosis. To identify the genetic changes that drive this transformation, we sequenced the exomes of 12 cases with paired FL and tFL biopsies and identified 45 recurrently mutated genes in the FL-tFL data set and 39 in the tFL cases. We selected 496 genes of potential importance in transformation and sequenced them in 23 additional tFL cases. Integration of the mutation data with copy-number abnormality (CNA) data provided complementary information...
July 8, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Claudia Otto, René Scholtysik, Roland Schmitz, Markus Kreuz, Claudia Becher, Michael Hummel, Andreas Rosenwald, Lorenz Trümper, Wolfram Klapper, Reiner Siebert, Ralf Küppers
Chromosomal translocations involving an immunoglobulin (IG) locus and a proto-oncogene play a major role in diffuse large B-cell lymphoma (DLBCL) pathogenesis. Recurrent IG translocation partners in DLBCL are the BCL6, BCL2, and MYC genes, but other rare translocation partners are also known. We studied 20 DLBCL with fluorescence in situ hybridization-based evidence for IG heavy chain (IGH) locus-associated translocations not involving BCL6, BCL2, MALT1, or MYC by long distance inverse PCR to identify the translocation partners...
June 29, 2016: Genes, Chromosomes & Cancer
Katharina Engel, Martina Rudelius, Jolanta Slawska, Laura Jacobs, Behnaz Ahangarian Abhari, Bettina Altmann, Julia Kurutz, Abirami Rathakrishnan, Vanesa Fernández-Sáiz, Andrä Brunner, Bianca-Sabrina Targosz, Felicia Loewecke, Christian Johannes Gloeckner, Marius Ueffing, Simone Fulda, Michael Pfreundschuh, Lorenz Trümper, Wolfram Klapper, Ulrich Keller, Philipp J Jost, Andreas Rosenwald, Christian Peschel, Florian Bassermann
The mitotic spindle assembly checkpoint (SAC) maintains genome stability and marks an important target for antineoplastic therapies. However, it has remained unclear how cells execute cell fate decisions under conditions of SAC-induced mitotic arrest. Here, we identify USP9X as the mitotic deubiquitinase of the X-linked inhibitor of apoptosis protein (XIAP) and demonstrate that deubiquitylation and stabilization of XIAP by USP9X lead to increased resistance toward mitotic spindle poisons. We find that primary human aggressive B-cell lymphoma samples exhibit high USP9X expression that correlate with XIAP overexpression...
2016: EMBO Molecular Medicine
F Röhrig, S Vorlová, H Hoffmann, M Wartenberg, F E Escorcia, S Keller, M Tenspolde, I Weigand, S Gätzner, K Manova, O Penack, D A Scheinberg, A Rosenwald, S Ergün, Z Granot, E Henke
The inadequate transport of drugs into the tumor tissue caused by its abnormal vasculature is a major obstacle to the treatment of cancer. Anti-vascular endothelial growth factor (anti-VEGF) drugs can cause phenotypic alteration and maturation of the tumor's vasculature. However, whether this consistently improves delivery and subsequent response to therapy is still controversial. Clinical results indicate that not all patients benefit from antiangiogenic treatment, necessitating the development of criteria to predict the effect of these agents in individual tumors...
June 6, 2016: Oncogene
Janine Schmidt, Shunyou Gong, Teresa Marafioti, Barbara Mankel, Blanca Gonzalez-Farre, Olga Balagué, Ana Mozos, José Cabeçadas, Jon van der Walt, Daniela Hoehn, Andreas Rosenwald, German Ott, Stefan Dojcinov, Caoimhe Egan, Ferran Nadeu, Joan Enric Ramis-Zaldívar, Guillem Clot, Carmen Bárcena, Vanesa Pérez-Alonso, Volker Endris, Roland Penzel, Carmen Lome-Maldonado, Irina Bonzheim, Falko Fend, Elias Campo, Elaine S Jaffe, Itziar Salaverria, Leticia Quintanilla-Martinez
Pediatric-type follicular lymphoma (PTFL) is a variant of follicular lymphoma (FL) with distinctive clinicopathological features. Patients are predominantly young males presenting with localized lymphadenopathy; the tumor shows high-grade cytology and lacks both BCL2 expression and t(14;18) translocation. The genetic alterations involved in the pathogenesis of PTFL are unknown. Therefore, 42 PTFL (40 males and 2 females; mean age, 16 years; range, 5-31) were genetically characterized. For comparison, 11 cases of conventional t(14:18)(-) FL in adults were investigated...
August 25, 2016: Blood
Sarah Keppler, Susann Weiβbach, Christian Langer, Stefan Knop, Jordan Pischimarov, Miriam Kull, Thorsten Stühmer, Torsten Steinbrunn, Ralf Bargou, Hermann Einsele, Andreas Rosenwald, Ellen Leich
Multiple myeloma (MM) is a plasma cell disorder that is characterized by a great genetic heterogeneity. Recent next generation sequencing studies revealed an accumulation of tumor-associated mutations in receptor tyrosine kinases (RTKs) which may also contribute to the activation of survival pathways in MM. To investigate the clinical role of RTK-mutations in MM, we deep-sequenced the coding DNA-sequence of EGFR, EPHA2, ERBB3, IGF1R, NTRK1 and NTRK2 which were previously found to be mutated in MM, in 75 uniformly treated MM patients of the "Deutsche Studiengruppe Multiples Myelom"...
May 26, 2016: Oncotarget
F Iltzsche, K Simon, S Stopp, G Pattschull, S Francke, P Wolter, S Hauser, D J Murphy, P Garcia, A Rosenwald, S Gaubatz
The conserved Myb-MuvB (MMB) multiprotein complex has an important role in transcriptional activation of mitotic genes. MMB target genes are overexpressed in several different cancer types and their elevated expression is associated with an advanced tumor state and a poor prognosis. This suggests that MMB could contribute to tumorigenesis by mediating overexpression of mitotic genes. However, although MMB has been extensively characterized biochemically, the requirement for MMB in tumorigenesis in vivo has not been investigated...
May 23, 2016: Oncogene
K Koch, E Hoster, M Ziepert, M Unterhalt, G Ott, A Rosenwald, M L Hansmann, W Bernd, H Stein, V Pöschel, M Dreyling, L Trümper, M Löffler, N Schmitz, W Hiddemann, M Pfreundschuh, W Klapper
BACKGROUND: Histologically, follicular lymphoma (FL) grades 1, 2 and 3A are composed of two distinct cell types, centroblasts and centrocytes. FL grade 3B is composed only of centroblasts and has been shown to differ in immunophenotype and genetics from FL that contain centrocytes. We aimed to understand the pathogenetic and clinical relation between FL grade 3A to FL grade 1/2 on the one hand and FL grade 3B on the other hand. PATIENTS AND METHODS: Trial patients with long-term follow-up and diagnosis of FL grade 3 were selected and samples underwent a second central pathological review using a multiple-observer approach to assess grading...
July 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Yibin Yang, Priscilla Kelly, Arthur L Shaffer, Roland Schmitz, Hee Min Yoo, Xinyue Liu, Da Wei Huang, Daniel Webster, Ryan M Young, Masao Nakagawa, Michele Ceribelli, George W Wright, Yandan Yang, Hong Zhao, Xin Yu, Weihong Xu, Wing C Chan, Elaine S Jaffe, Randy D Gascoyne, Elias Campo, Andreas Rosenwald, German Ott, Jan Delabie, Lisa Rimsza, Louis M Staudt
Chronic active B cell receptor (BCR) signaling, a hallmark of the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), engages the CARD11-MALT1-BCL10 (CBM) adapter complex to activate IκB kinase (IKK) and the classical NF-κB pathway. Here we show that the CBM complex includes the E3 ubiquitin ligases cIAP1 and cIAP2, which are essential mediators of BCR-dependent NF-κB activity in ABC DLBCL. cIAP1/2 attach K63-linked polyubiquitin chains on themselves and on BCL10, resulting in the recruitment of IKK and the linear ubiquitin chain ligase LUBAC, which is essential for IKK activation...
April 11, 2016: Cancer Cell
Leo Rasche, Emmanuelle Menoret, Valentina Dubljevic, Eline Menu, Karin Vanderkerken, Constantin Lapa, Torsten Steinbrunn, Manik Chatterjee, Stefan Knop, Johannes Düll, Deanne L Greenwood, Frank Hensel, Andreas Rosenwald, Hermann Einsele, Stephanie Brändlein
PURPOSE: Glucose-regulated protein (GRP) 78 is overexpressed in multiple myeloma, and both its surface expression and its biologic significance as key sensor of the unfolded protein response make GRP78 an ideal candidate for immunotherapeutic intervention. The monoclonal antibody PAT-SM6 targets surface GRP78 and leads to disease stabilization when used as single agent in a clinical trial. In this article, we evaluated expression of GRP78 in relapsed-refractory disease and explored PAT-SM6 therapy in combination regimens...
September 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Eva Hoster, Andreas Rosenwald, Françoise Berger, Heinz-Wolfram Bernd, Sylvia Hartmann, Christoph Loddenkemper, Thomas F E Barth, Nicole Brousse, Stefano Pileri, Grzegorz Rymkiewicz, Roman Kodet, Stephan Stilgenbauer, Roswitha Forstpointner, Catherine Thieblemont, Michael Hallek, Bertrand Coiffier, Ursula Vehling-Kaiser, Réda Bouabdallah, Lothar Kanz, Michael Pfreundschuh, Christian Schmidt, Vincent Ribrag, Wolfgang Hiddemann, Michael Unterhalt, Johanna C Kluin-Nelemans, Olivier Hermine, Martin H Dreyling, Wolfram Klapper
PURPOSE: Mantle-cell lymphoma (MCL) is a rather aggressive B-cell malignancy whose considerable variability of individual outcome is associated with clinical characteristics (Mantle Cell Lymphoma International Prognostic Index [MIPI]). The Ki-67 index is a strong independent prognostic factor; however, the biologic MIPI (MIPI-b) distinguishes only two groups, which does not appropriately depict the clinical heterogeneity. By using the cohort from the European MCL Younger and MCL Elderly trials, we aimed to evaluate the additional prognostic impact of cytology and growth pattern and to improve risk stratification with the Ki-67 index and MIPI...
April 20, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
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