TY - JOUR A1 - Walker, Brian A. A1 - Mavrommatis, Konstantinos A1 - Wardell, Christopher P. A1 - Ashby, T. Cody A1 - Bauer, Michael A1 - Davies, Faith A1 - Rosenthal, Adam A1 - Wang, Hongwei A1 - Qu, Pingping A1 - Hoering, Antje A1 - Samur, Mehmet A1 - Towfic, Fadi A1 - Ortiz, Maria A1 - Flynt, Erin A1 - Yu, Zhinuan A1 - Yang, Zhihong A1 - Rozelle, Dan A1 - Obenauer, John A1 - Trotter, Matthew A1 - Auclair, Daniel A1 - Keats, Jonathan A1 - Bolli, Niccolo A1 - Fulciniti, Mariateresa A1 - Szalat, Raphael A1 - Moreau, Phillipe A1 - Durie, Brian A1 - Stewart, A. Keith A1 - Goldschmidt, Hartmut A1 - Raab, Marc S. A1 - Einsele, Hermann A1 - Sonneveld, Pieter A1 - San Miguel, Jesus A1 - Lonial, Sagar A1 - Jackson, Graham H. A1 - Anderson, Kenneth C. A1 - Avet-Loiseau, Herve A1 - Munshi, Nikhil A1 - Thakurta, Anjan A1 - Morgan, Gareth T1 - A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis JF - Leukemia N2 - Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Whole-genome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R2 = 18.4% and 25.2%, respectively). Integrating DNA drivers and clinical data into a Cox model using 784 patients with ISS, age, PFS, OS, and genomic data, the model has a cumlative R2 of 34.3% for PFS and 46.5% for OS. A high-risk subgroup was defined by recursive partitioning using either a) bi-allelic TP53 inactivation or b) amplification (≥4 copies) of CKS1B (1q21) on the background of International Staging System III, comprising 6.1% of the population (median PFS = 15.4 months; OS = 20.7 months) that was validated in an independent dataset. Double-Hit patients have a dire prognosis despite modern therapies and should be considered for novel therapeutic approaches. KW - cancer genomics KW - risk factors Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233299 VL - 33 ER - TY - JOUR A1 - Nerreter, Thomas A1 - Letschert, Sebastian A1 - Götz, Ralph A1 - Doose, Sören A1 - Danhof, Sophia A1 - Einsele, Hermann A1 - Sauer, Markus A1 - Hudecek, Michael T1 - Super-resolution microscopy reveals ultra-low CD19 expression on myeloma cells that triggers elimination by CD19 CAR-T JF - Nature Communications N2 - Immunotherapy with chimeric antigen receptor-engineered T-cells (CAR-T) is under investigation in multiple myeloma. There are reports of myeloma remission after CD19 CAR-T therapy, although CD19 is hardly detectable on myeloma cells by flow cytometry (FC). We apply single molecule-sensitive direct stochastic optical reconstruction microscopy (dSTORM), and demonstrate CD19 expression on a fraction of myeloma cells (10.3–80%) in 10 out of 14 patients (density: 13–5,000 molecules per cell). In contrast, FC detects CD19 in only 2 of these 10 patients, on a smaller fraction of cells. Treatment with CD19 CAR-T in vitro results in elimination of CD19-positive myeloma cells, including those with <100 CD19 molecules per cell. Similar data are obtained by dSTORM analyses of CD20 expression on myeloma cells and CD20 CAR-T. These data establish a sensitivity threshold for CAR-T and illustrate how super-resolution microscopy can guide patient selection in immunotherapy to exploit ultra-low density antigens. KW - cancer imaging KW - cancer immunotherapy KW - imaging Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232258 VL - 10 ER - TY - JOUR A1 - Medler, Juliane A1 - Nelke, Johannes A1 - Weisenberger, Daniela A1 - Steinfatt, Tim A1 - Rothaug, Moritz A1 - Berr, Susanne A1 - Hünig, Thomas A1 - Beilhack, Andreas A1 - Wajant, Harald T1 - TNFRSF receptor-specific antibody fusion proteins with targeting controlled FcγR-independent agonistic activity JF - Cell Death & Disease N2 - Antibodies specific for TNFRSF receptors that bind soluble ligands without getting properly activated generally act as strong agonists upon FcγR binding. Systematic analyses revealed that the FcγR dependency of such antibodies to act as potent agonists is largely independent from isotype, FcγR type, and of the epitope recognized. This suggests that the sole cellular attachment, achieved by Fc domain-FcγR interaction, dominantly determines the agonistic activity of antibodies recognizing TNFRSF receptors poorly responsive to soluble ligands. In accordance with this hypothesis, we demonstrated that antibody fusion proteins harboring domains allowing FcγR-independent cell surface anchoring also act as strong agonist provided they have access to their target. This finding defines a general possibility to generate anti-TNFRSF receptor antibodies with FcγR-independent agonism. Moreover, anti-TNFRSF receptor antibody fusion proteins with an anchoring domain promise superior applicability to conventional systemically active agonists when an anchoring target with localized disease associated expression can be addressed. KW - biologics KW - proteins Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223948 VL - 10 ER - TY - JOUR A1 - López, Cristina A1 - Kleinheinz, Kortine A1 - Aukema, Sietse M. A1 - Rohde, Marius A1 - Bernhart, Stephan H. A1 - Hübschmann, Daniel A1 - Wagener, Rabea A1 - Toprak, Umut H. A1 - Raimondi, Francesco A1 - Kreuz, Markus A1 - Waszak, Sebastian M. A1 - Huang, Zhiqin A1 - Sieverling, Lina A1 - Paramasivam, Nagarajan A1 - Seufert, Julian A1 - Sungalee, Stephanie A1 - Russell, Robert B. A1 - Bausinger, Julia A1 - Kretzmer, Helene A1 - Ammerpohl, Ole A1 - Bergmann, Anke K. A1 - Binder, Hans A1 - Borkhardt, Arndt A1 - Brors, Benedikt A1 - Claviez, Alexander A1 - Doose, Gero A1 - Feuerbach, Lars A1 - Haake, Andrea A1 - Hansmann, Martin-Leo A1 - Hoell, Jessica A1 - Hummel, Michael A1 - Korbel, Jan O. A1 - Lawerenz, Chris A1 - Lenze, Dido A1 - Radlwimmer, Bernhard A1 - Richter, Julia A1 - Rosenstiel, Philip A1 - Rosenwald, Andreas A1 - Schilhabel, Markus B. A1 - Stein, Harald A1 - Stilgenbauer, Stephan A1 - Stadler, Peter F. A1 - Szczepanowski, Monika A1 - Weniger, Marc A. A1 - Zapatka, Marc A1 - Eils, Roland A1 - Lichter, Peter A1 - Loeffler, Markus A1 - Möller, Peter A1 - Trümper, Lorenz A1 - Klapper, Wolfram A1 - Hoffmann, Steve A1 - Küppers, Ralf A1 - Burkhardt, Birgit A1 - Schlesner, Matthias A1 - Siebert, Reiner T1 - Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma JF - Nature Communications N2 - Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing. KW - cancer genomics KW - lymphocytes KW - lymphoid tissues KW - oncology Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237281 VL - 10 ER - TY - JOUR A1 - El-Helou, Sabine M. A1 - Biegner, Anika-Kerstin A1 - Bode, Sebastian A1 - Ehl, Stephan R. A1 - Heeg, Maximilian A1 - Maccari, Maria E. A1 - Ritterbusch, Henrike A1 - Speckmann, Carsten A1 - Rusch, Stephan A1 - Scheible, Raphael A1 - Warnatz, Klaus A1 - Atschekzei, Faranaz A1 - Beider, Renata A1 - Ernst, Diana A1 - Gerschmann, Stev A1 - Jablonka, Alexandra A1 - Mielke, Gudrun A1 - Schmidt, Reinhold E. A1 - Schürmann, Gesine A1 - Sogkas, Georgios A1 - Baumann, Ulrich H. A1 - Klemann, Christian A1 - Viemann, Dorothee A1 - Bernuth, Horst von A1 - Krüger, Renate A1 - Hanitsch, Leif G. A1 - Scheibenbogen, Carmen M. A1 - Wittke, Kirsten A1 - Albert, Michael H. A1 - Eichinger, Anna A1 - Hauck, Fabian A1 - Klein, Christoph A1 - Rack-Hoch, Anita A1 - Sollinger, Franz M. A1 - Avila, Anne A1 - Borte, Michael A1 - Borte, Stephan A1 - Fasshauer, Maria A1 - Hauenherm, Anja A1 - Kellner, Nils A1 - Müller, Anna H. A1 - Ülzen, Anett A1 - Bader, Peter A1 - Bakhtiar, Shahrzad A1 - Lee, Jae-Yun A1 - Heß, Ursula A1 - Schubert, Ralf A1 - Wölke, Sandra A1 - Zielen, Stefan A1 - Ghosh, Sujal A1 - Laws, Hans-Juergen A1 - Neubert, Jennifer A1 - Oommen, Prasad T. A1 - Hönig, Manfred A1 - Schulz, Ansgar A1 - Steinmann, Sandra A1 - Klaus, Schwarz A1 - Dückers, Gregor A1 - Lamers, Beate A1 - Langemeyer, Vanessa A1 - Niehues, Tim A1 - Shai, Sonu A1 - Graf, Dagmar A1 - Müglich, Carmen A1 - Schmalzing, Marc T. A1 - Schwaneck, Eva C. A1 - Tony, Hans-Peter A1 - Dirks, Johannes A1 - Haase, Gabriele A1 - Liese, Johannes G. A1 - Morbach, Henner A1 - Foell, Dirk A1 - Hellige, Antje A1 - Wittkowski, Helmut A1 - Masjosthusmann, Katja A1 - Mohr, Michael A1 - Geberzahn, Linda A1 - Hedrich, Christian M. A1 - Müller, Christiane A1 - Rösen-Wolff, Angela A1 - Roesler, Joachim A1 - Zimmermann, Antje A1 - Behrends, Uta A1 - Rieber, Nikolaus A1 - Schauer, Uwe A1 - Handgretinger, Rupert A1 - Holzer, Ursula A1 - Henes, Jörg A1 - Kanz, Lothar A1 - Boesecke, Christoph A1 - Rockstroh, Jürgen K. A1 - Schwarze-Zander, Carolynne A1 - Wasmuth, Jan-Christian A1 - Dilloo, Dagmar A1 - Hülsmann, Brigitte A1 - Schönberger, Stefan A1 - Schreiber, Stefan A1 - Zeuner, Rainald A1 - Ankermann, Tobias A1 - Bismarck, Philipp von A1 - Huppertz, Hans-Iko A1 - Kaiser-Labusch, Petra A1 - Greil, Johann A1 - Jakoby, Donate A1 - Kulozik, Andreas E. A1 - Metzler, Markus A1 - Naumann-Bartsch, Nora A1 - Sobik, Bettina A1 - Graf, Norbert A1 - Heine, Sabine A1 - Kobbe, Robin A1 - Lehmberg, Kai A1 - Müller, Ingo A1 - Herrmann, Friedrich A1 - Horneff, Gerd A1 - Klein, Ariane A1 - Peitz, Joachim A1 - Schmidt, Nadine A1 - Bielack, Stefan A1 - Groß-Wieltsch, Ute A1 - Classen, Carl F. A1 - Klasen, Jessica A1 - Deutz, Peter A1 - Kamitz, Dirk A1 - Lassy, Lisa A1 - Tenbrock, Klaus A1 - Wagner, Norbert A1 - Bernbeck, Benedikt A1 - Brummel, Bastian A1 - Lara-Villacanas, Eusebia A1 - Münstermann, Esther A1 - Schneider, Dominik T. A1 - Tietsch, Nadine A1 - Westkemper, Marco A1 - Weiß, Michael A1 - Kramm, Christof A1 - Kühnle, Ingrid A1 - Kullmann, Silke A1 - Girschick, Hermann A1 - Specker, Christof A1 - Vinnemeier-Laubenthal, Elisabeth A1 - Haenicke, Henriette A1 - Schulz, Claudia A1 - Schweigerer, Lothar A1 - Müller, Thomas G. A1 - Stiefel, Martina A1 - Belohradsky, Bernd H. A1 - Soetedjo, Veronika A1 - Kindle, Gerhard A1 - Grimbacher, Bodo T1 - The German national registry of primary immunodeficiencies (2012-2017) JF - Frontiers in Immunology N2 - Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1-25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0-88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE-syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%-subcutaneous; 29%-intravenous; 1%-unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment. KW - registry for primary immunodeficiency KW - primary immunodeficiency (PID) KW - German PID-NET registry KW - PID prevalence KW - European Society for Immunodeficiencies (ESID) KW - IgG substitution therapy KW - CVID Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226629 VL - 10 ER - TY - JOUR A1 - Cook, Nigel A1 - Geier, Andreas A1 - Schmid, Andreas A1 - Hirschfeld, Gideon A1 - Kautz, Achim A1 - Schattenberg, Jörn M. A1 - Balp, Maria-Magdalena T1 - The patient perspectives on future therapeutic options in NASH and patient needs JF - Frontiers in Medicine N2 - Background: Non-alcoholic steatohepatitis (NASH) is a chronic liver disease with severe complications and without approved therapies. Currently, there is limited data on the overall burden of the disease for patients or on patient needs and preferences. This study investigates patient preferences in relation to potential future therapies for NASH. In addition, the factors that are relevant to patients and their importance in relation to future treatment options are explored. Method: Telephone in-depth interviews (TDIs) preceded an online 30-min quantitative survey. The online survey included (1) multiple choice questions (MCQs) on NASH diagnosis and disease background. (2) An exercise to determine patients' satisfaction levels with information provided at diagnosis, and to explore symptomatology in detail. (3) Exercises to evaluate potential new products and product attributes, including a "drag and drop" ranking exercise, and an adaptive choice-based conjoint exercise (ACBC). (4) The EQ-5D-5L questionnaire and the Visual Analog Scale (VAS), which measures patients' health status. (5) Collection of socio-demographic data, and (6) Questions to measure patient satisfaction with the survey. Results: There were 166 patients included in this study from Canada [n = 36], Germany [n = 50], the UK [n = 30], and USA [n = 50]. Fifty seven percent of patients [n = 94] had had a liver biopsy for confirmation of NASH. Patients were often unable to link their symptoms to NASH or other conditions. ACBC results showed that efficacy, defined as "impact on liver status" was the single most important attribute of a potential future NASH therapy. Other attributes considered to have secondary importance included impact on weight, symptom control and the presence of side effects. The EQ-5D utility score was 0.81 and VAS = 67.2. Conclusion: "Impact on liver status" is the primary outcome sought. Patients demonstrate a general lack of understanding of their disease and appeared to be unfamiliar with longer-term consequences of NASH. It is necessary to improve patient understanding of NASH and its progressive nature, and there is a need for improving confirmatory diagnosis and monitoring. KW - patient preference KW - non-alcoholic fatty liver disease (NAFLD) KW - non-alcoholic steatohepatitis (NASH) KW - adaptive choice-based conjoint KW - liver disease KW - EQ5D-5L KW - patient-based evidence KW - patient-reported outcomes Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223268 VL - 6 ER - TY - JOUR A1 - Kraus, Amelie J. A1 - Brink, Benedikt G. A1 - Siegel, T. Nicolai T1 - Efficient and specific oligo-based depletion of rRNA JF - Scientific Reports N2 - In most organisms, ribosomal RNA (rRNA) contributes to >85% of total RNA. Thus, to obtain useful information from RNA-sequencing (RNA-seq) analyses at reasonable sequencing depth, typically, mature polyadenylated transcripts are enriched or rRNA molecules are depleted. Targeted depletion of rRNA is particularly useful when studying transcripts lacking a poly(A) tail, such as some non-coding RNAs (ncRNAs), most bacterial RNAs and partially degraded or immature transcripts. While several commercially available kits allow effective rRNA depletion, their efficiency relies on a high degree of sequence homology between oligonucleotide probes and the target RNA. This restricts the use of such kits to a limited number of organisms with conserved rRNA sequences. In this study we describe the use of biotinylated oligos and streptavidin-coated paramagnetic beads for the efficient and specific depletion of trypanosomal rRNA. Our approach reduces the levels of the most abundant rRNA transcripts to less than 5% with minimal off-target effects. By adjusting the sequence of the oligonucleotide probes, our approach can be used to deplete rRNAs or other abundant transcripts independent of species. Thus, our protocol provides a useful alternative for rRNA removal where enrichment of polyadenylated transcripts is not an option and commercial kits for rRNA are not available. KW - parasite biology KW - RNA sequencing KW - transcriptomics Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224829 VL - 9 ER - TY - JOUR A1 - Knop, Janin A1 - Spilgies, Lisanne M. A1 - Rufli, Stefanie A1 - Reinhart, Ramona A1 - Vasilikos, Lazaros A1 - Yabal, Monica A1 - Owsley, Erika A1 - Jost, Philipp J. A1 - Marsh, Rebecca A. A1 - Wajant, Harald A1 - Robinson, Mark D. A1 - Kaufmann, Thomas A1 - W. Wei-Lynn, Wong T1 - TNFR2 induced priming of the inflammasome leads to a RIPK1-dependent cell death in the absence of XIAP JF - Cell Death & Disease N2 - The pediatric immune deficiency X-linked proliferative disease-2 (XLP-2) is a unique disease, with patients presenting with either hemophagocytic lymphohistiocytosis (HLH) or intestinal bowel disease (IBD). Interestingly, XLP-2 patients display high levels of IL-18 in the serum even while in stable condition, presumably through spontaneous inflammasome activation. Recent data suggests that LPS stimulation can trigger inflammasome activation through a TNFR2/TNF/TNFR1 mediated loop in xiap−/− macrophages. Yet, the direct role TNFR2-specific activation plays in the absence of XIAP is unknown. We found TNFR2-specific activation leads to cell death in xiap−/− myeloid cells, particularly in the absence of the RING domain. RIPK1 kinase activity downstream of TNFR2 resulted in a TNF/TNFR1 cell death, independent of necroptosis. TNFR2-specific activation leads to a similar inflammatory NF-kB driven transcriptional profile as TNFR1 activation with the exception of upregulation of NLRP3 and caspase-11. Activation and upregulation of the canonical inflammasome upon loss of XIAP was mediated by RIPK1 kinase activity and ROS production. While both the inhibition of RIPK1 kinase activity and ROS production reduced cell death, as well as release of IL-1β, the release of IL-18 was not reduced to basal levels. This study supports targeting TNFR2 specifically to reduce IL-18 release in XLP-2 patients and to reduce priming of the inflammasome components. KW - cell death and immune response KW - inflammation Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325946 VL - 10 ER - TY - JOUR A1 - Gotru, Sanjeev Kiran A1 - van Geffen, Johanna P. A1 - Nagy, Magdolna A1 - Mammadova-Bach, Elmina A1 - Eilenberger, Julia A1 - Volz, Julia A1 - Manukjan, Georgi A1 - Schulze, Harald A1 - Wagner, Leonard A1 - Eber, Stefan A1 - Schambeck, Christian A1 - Deppermann, Carsten A1 - Brouns, Sanne A1 - Nurden, Paquita A1 - Greinacher, Andreas A1 - Sachs, Ulrich A1 - Nieswandt, Bernhard A1 - Hermanns, Heike M. A1 - Heemskerk, Johan W. M. A1 - Braun, Attila T1 - Defective Zn2+ homeostasis in mouse and human platelets with α- and δ-storage pool diseases JF - Scientific Reports N2 - Zinc (Zn2+) can modulate platelet and coagulation activation pathways, including fibrin formation. Here, we studied the (patho)physiological consequences of abnormal platelet Zn2+ storage and release. To visualize Zn2+ storage in human and mouse platelets, the Zn2+ specific fluorescent dye FluoZin3 was used. In resting platelets, the dye transiently accumulated into distinct cytosolic puncta, which were lost upon platelet activation. Platelets isolated from Unc13d−/− mice, characterized by combined defects of α/δ granular release, showed a markedly impaired Zn2+ release upon activation. Platelets from Nbeal2−/− mice mimicking Gray platelet syndrome (GPS), characterized by primarily loss of the α-granule content, had strongly reduced Zn2+ levels, which was also confirmed in primary megakaryocytes. In human platelets isolated from patients with GPS, Hermansky-Pudlak Syndrome (HPS) and Storage Pool Disease (SPD) altered Zn2+ homeostasis was detected. In turbidity and flow based assays, platelet-dependent fibrin formation was impaired in both Nbeal2−/− and Unc13d−/− mice, and the impairment could be partially restored by extracellular Zn2+. Altogether, we conclude that the release of ionic Zn2+ store from secretory granules upon platelet activation contributes to the procoagulant role of Zn2+ in platelet-dependent fibrin formation. KW - coagulation system KW - metals Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227455 VL - 9 ER - TY - JOUR A1 - El-Mesery, Mohamed A1 - Rosenthal, Tina A1 - Rauert-Wunderlich, Hilka A1 - Schreder, Martin A1 - Stühmer, Thorsten A1 - Leich, Ellen A1 - Schlosser, Andreas A1 - Ehrenschwender, Martin A1 - Wajant, Harald A1 - Siegmund, Daniela T1 - The NEDD8-activating enzyme inhibitor MLN4924 sensitizes a TNFR1+ subgroup of multiple myeloma cells for TNF-induced cell death JF - Cell Death & Disease N2 - The NEDD8-activating enzyme (NAE) inhibitor MLN4924 inhibits cullin-RING ubiquitin ligase complexes including the SKP1-cullin-F-box E3 ligase βTrCP. MLN4924 therefore inhibits also the βTrCP-dependent activation of the classical and the alternative NFĸB pathway. In this work, we found that a subgroup of multiple myeloma cell lines (e.g., RPMI-8226, MM.1S, KMS-12BM) and about half of the primary myeloma samples tested are sensitized to TNF-induced cell death by MLN4924. This correlated with MLN4924-mediated inhibition of TNF-induced activation of the classical NFκB pathway and reduced the efficacy of TNF-induced TNFR1 signaling complex formation. Interestingly, binding studies revealed a straightforward correlation between cell surface TNFR1 expression in multiple myeloma cell lines and their sensitivity for MLN4924/TNF-induced cell death. The cell surface expression levels of TNFR1 in the investigated MM cell lines largely correlated with TNFR1 mRNA expression. This suggests that the variable levels of cell surface expression of TNFR1 in myeloma cell lines are decisive for TNF/MLN4924 sensitivity. Indeed, introduction of TNFR1 into TNFR1-negative TNF/MLN4924-resistant KMS-11BM cells, was sufficient to sensitize this cell line for TNF/MLN4924-induced cell death. Thus, MLN4924 might be especially effective in myeloma patients with TNFR1+ myeloma cells and a TNFhigh tumor microenvironment. KW - cancer therapy KW - tumour-necrosis factors Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226666 VL - 10 ER -