TY - JOUR A1 - Effenberger, Madlen A1 - Bommert, Kathryn S. A1 - Kunz, Viktoria A1 - Kruk, Jessica A1 - Leich, Ellen A1 - Rudelius, Martina A1 - Bargou, Ralf A1 - Bommert, Kurt T1 - Glutaminase inhibition in multiple myeloma induces apoptosis via MYC degradation JF - Oncotarget N2 - Multiple Myeloma (MM) is an incurable hematological malignancy affecting millions of people worldwide. As in all tumor cells both glucose and more recently glutamine have been identified as important for MM cellular metabolism, however there is some dispute as to the role of glutamine in MM cell survival. Here we show that the small molecule inhibitor compound 968 effectively inhibits glutaminase and that this inhibition induces apoptosis in both human multiple myeloma cell lines (HMCLs) and primary patient material. The HMCL U266 which does not express MYC was insensitive to both glutamine removal and compound 968, but ectopic expression of MYC imparted sensitivity. Finally, we show that glutamine depletion is reflected by rapid loss of MYC protein which is independent of MYC transcription and post translational modifications. However, MYC loss is dependent on proteasomal activity, and this loss was paralleled by an equally rapid induction of apoptosis. These findings are in contrast to those of glucose depletion which largely affected rates of proliferation in HMCLs, but had no effects on either MYC expression or viability. Therefore, inhibition of glutaminolysis is effective at inducing apoptosis and thus serves as a possible therapeutic target in MM. KW - Multiple Myeloma KW - glutaminase inhibition KW - apoptosis KW - MYC Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170168 VL - 8 IS - 49 ER - TY - JOUR A1 - Franke, Katharina A1 - Vilne, Baiba A1 - da Costa, Olivia Prazeres A1 - Rudelius, Martina A1 - Peschel, Christian A1 - Oostendorp, Robert A. J. A1 - Keller, Ulrich T1 - In vivo hematopoietic Myc activation directs a transcriptional signature in endothelial cells within the bone marrow microenvironment JF - Oncotarget N2 - Cancer pathogenesis involves tumor-intrinsic genomic aberrations and tumor-cell extrinsic mechanisms such as failure of immunosurveillance and structural and functional changes in the microenvironment. Using Myc as a model oncogene we established a conditional mouse bone marrow transduction/transplantation model where the conditional activation of the oncoprotein Myc expressed in the hematopoietic system could be assessed for influencing the host microenvironment. Constitutive ectopic expression of Myc resulted in rapid onset of a lethal myeloproliferative disorder with a median survival of 21 days. In contrast, brief 4-day Myc activation by means of the estrogen receptor (ER) agonist tamoxifen did not result in gross changes in the percentage/frequency of hematopoietic lineages or hematopoietic stem/progenitor cell (HSPC) subsets, nor did Myc activation significantly change the composition of the non-hematopoietic microenvironment defined by phenotyping for CD31, ALCAM, and Sca-1 expression. Transcriptome analysis of endothelial CD45-Ter119-cells from tamoxifen-treated MycER bone marrow graft recipients revealed a gene expression signature characterized by specific changes in the Rho subfamily pathway members, in the transcription-translation-machinery and in angiogenesis. In conclusion, intra-hematopoietic Myc activation results in significant transcriptome alterations that can be attributed to oncogene-induced signals from hematopoietic cells towards the microenvironment, e. g. endothelial cells, supporting the idea that even pre-leukemic HSPC highjack components of the niche which then could protect and support the cancer-initiating population. KW - stem-cells KW - mutations KW - C-Myc KW - Rho-GTPases KW - niche KW - leukemia KW - target KW - growth KW - cycle KW - apoptosis, Myc KW - microenvironment KW - endothelial cells Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145844 VL - 6 IS - 26 SP - 21827 EP - 21839 ER - TY - JOUR A1 - Werner, Rudolf A. A1 - Weich, Alexander A1 - Higuchi, Takahiro A1 - Schmid, Jan S. A1 - Schirbel, Andreas A1 - Lassmann, Michael A1 - Wild, Vanessa A1 - Rudelius, Martina A1 - Kudlich, Theodor A1 - Herrmann, Ken A1 - Scheurlen, Michael A1 - Buck, Andreas K. A1 - Kropf, Saskia A1 - Wester, Hans-Jürgen A1 - Lapa, Constantin T1 - Imaging of Chemokine Receptor 4 Expression in Neuroendocrine Tumors - a Triple Tracer Comparative Approach JF - Theranostics N2 - C-X-C motif chemokine receptor 4 (CXCR4) and somatostatin receptors (SSTR) are overexpressed in gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). In this study, we aimed to elucidate the feasibility of non-invasive CXCR4 positron emission tomography/computed tomography (PET/CT) imaging in GEP-NET patients using [\(^{68}\)Ga]Pentixafor in comparison to \(^{68}\)Ga-DOTA-D-Phe-Tyr3-octreotide ([\(^{68}\)Ga]DOTATOC) and \(^{18}\)F-fluorodeoxyglucose ([\(^{18}\)F]FDG). Twelve patients with histologically proven GEP-NET (3xG1, 4xG2, 5xG3) underwent [\(^{68}\)Ga]DOTATOC, [\(^{18}\)F]FDG, and [\(^{68}\)Ga]Pentixafor PET/CT for staging and planning of the therapeutic management. Scans were analyzed on a patient as well as on a lesion basis and compared to immunohistochemical staining patterns of CXCR4 and somatostatin receptors SSTR2a and SSTR5. [\(^{68}\)Ga]Pentixafor visualized tumor lesions in 6/12 subjects, whereas [\(^{18}\)F]FDG revealed sites of disease in 10/12 and [\(^{68}\)Ga]DOTATOC in 11/12 patients, respectively. Regarding sensitivity, SSTR-directed PET was the superior imaging modality in all G1 and G2 NET. CXCR4-directed PET was negative in all G1 NET. In contrast, 50% of G2 and 80% of G3 patients exhibited [\(^{68}\)Ga]Pentixafor-positive tumor lesions. Whereas CXCR4 seems to play only a limited role in detecting well-differentiated NET, increasing receptor expression could be non-invasively observed with increasing tumor grade. Thus, [\(^{68}\)Ga]Pentixafor PET/CT might serve as non-invasive read-out for evaluating the possibility of CXCR4-directed endoradiotherapy in advanced dedifferentiated SSTR-negative tumors. KW - SSTR KW - peptide receptor radionuclide therapy KW - neuroendocrine tumor KW - [\(^{68}\)Ga]Pentixafor KW - CXCR4 KW - chemokine receptor KW - PET/CT KW - DOTATOC KW - PRRT KW - Positronen-Emissions-Tomografie Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158008 VL - 7 IS - 6 ER - TY - JOUR A1 - Herrmann, Ken A1 - Buck, Andreas K. A1 - Schuster, Tibor A1 - Abbrederis, Kathrin A1 - Blümel, Christina A1 - Santi, Ivan A1 - Rudelius, Martina A1 - Wester, Hans-Jürgen A1 - Peschel, Christian A1 - Schwaiger, Markus A1 - Dechow, Tobias A1 - Keller, Ulrich T1 - Week one FLT-PET response predicts complete remission to R-CHOP and survival in DLBCL JF - Oncotarget N2 - Despite improved survival in the Rituximab (R) era, a considerable number of patients with diffuse large B-cell lymphoma (DLBCL) ultimately die from the disease. Functional imaging using [18F]fluorodeoxyglucose-PET is suggested for assessment of residual viable tumor very early during treatment but is compromised by non-specific tracer retention in inflammatory lesions. The PET tracer [18F]fluorodeoxythymidine (FLT) as surrogate marker of tumor proliferation may overcome this limitation. We present results of a prospective clinical study testing FLT-PET as superior and early predictor of response to chemotherapy and outcome in DLBCL. 54 patients underwent FLT-PET prior to and one week after the start of R-CHOP chemotherapy. Repetitive FLT-PET imaging was readily implemented into the diagnostic work-up. Our data demonstrate that the reduction of FLT standard uptake valuemean (SUVmean) and SUVmax one week after chemotherapy was significantly higher in patients achieving complete response (CR, n=48; non-CR, n=6; p<0.006). Martingale-residual and Cox proportional hazard analyses showed a significant monotonous decrease of mortality risk with increasing change in SUV. Consistent with these results, early FLT-PET response showed relevant discriminative ability in predicting CR. In conclusion, very early FLT-PET in the course of R-CHOP chemotherapy is feasible and enables identification of patients at risk for treatment failure. KW - [18F]Fluorodeoxythymidine KW - FLT-PET KW - positron emission tomography KW - DLBCL KW - lymphoma Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120659 SN - 1949-2553 VL - 5 IS - 12 ER - TY - JOUR A1 - Pickhard, Anja A1 - Siegl, Michael A1 - Baumann, Alexander A1 - Huhn, Maximilian A1 - Wirth, Markus A1 - Reiter, Rudolf A1 - Rudelius, Martina A1 - Piontek, Guido A1 - Brockhoff, Gero T1 - The response of head and neck squamous cell carcinoma to cetuximab treatment depends on Aurora kinase A polymorphism JF - Oncotarget N2 - Objectives: The aim of this study was to evaluate the efficiency of cetuximab-based anti-EGFR treatment and Aurora kinase A / B knockdown as a function of Aurora kinase polymorphism in HNSCC cell lines. Materials and methods: First, protein expression of Aurora kinase A / B and EGFR and Aurora kinase A polymorphism were studied in tumour samples. The survival and proliferation of Aurora kinase A homo- (Cal27) and heterozygous (HN) HNSCC cell lines was evaluated using a colony formation assay and a flow cytometric assay. Also, aneuploidy was determined. EGFR signalling pathway were visualised by western blotting. Results: Immunohistochemistry revealed the overexpression of Aurora kinase A / B in HNSCC. The knockdown of each kinase caused a significant decrease in clonogenic survival, independent of Aurora kinase A polymorphism. In contrast, cetuximab treatment impaired clonogenic survival only in the Aurora kinase A-homozygous cell line (Cal27). Conclusion: This study provides in vitro evidence for the predictive value of Aurora kinase A polymorphism in the efficiency of cetuximab treatment. Resistance to cetuximab treatment can be overcome by simultaneous Aurora kinase A/B knockdown. KW - aurora kinase A polymorphism KW - aurorakinase B KW - cetuximab KW - HNSCC Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120757 VL - 5 IS - 14 ER - TY - JOUR A1 - Schiefler, Carlotta A1 - Piontek, Guido A1 - Doescher, Johannes A1 - Schuettler, Dominik A1 - Mißlbeck, Martin A1 - Rudelius, Martina A1 - Haug, Anna A1 - Reiter, Rudolf A1 - Brockhoff, Gero A1 - Pickhard, Anja T1 - Inhibition of SphK1 reduces radiation-induced migration and enhances sensitivity to cetuximab treatment by affecting the EGFR/SphK1 crosstalk JF - Oncotarget N2 - SphK1 is known to play a role in tumor progression, resistance to radiochemotherapy, and migration patterns. As the overall survival rates of squamous cell carcinoma of the head and neck (HNSCC) remain poor due to limitations in surgery and irradiation and chemotherapy resistance, SphK1 is an important enzyme to investigate. The purpose of this study was to elucidate the impact of SphK1 on irradiation efficacy of HNSCC in-vitro with emphasis on EGFR signaling. By immunhistochemical staining we found a positive correlation between EGFR and SphK1 expression in patient specimens. In colony formation assays irradiation sensitive cell lines showed a poor response to cetuximab, an EGFR inhibitor, and SKI-II, a SphK1 inhibitor, and vice versa. In irradiation sensitive cells an enhanced reduction of cell migration and survival was found upon simultaneous targeting of EGFR and SphK1. In the present study, we elucidated a linkage between the two signaling pathways with regard to the efficacy of cetuximab treatment and the impact on the migration behavior of tumor cells. We investigated the biological impact of inhibiting these pathways and examined the biochemical implications after different treatments. An understanding of the processes involved could help to improve the treatment of patients with HNSCC. KW - radiation-induced migration KW - radiation KW - HNSCC KW - EGFR KW - SphK1 Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120929 SN - 1949-2553 VL - 5 IS - 20 ER - TY - JOUR A1 - Müller-Thomas, Catharina A1 - Rudelius, Martina A1 - Rondak, Ina-Christine A1 - Haferlach, Torsten A1 - Schanz, Julie A1 - Huberle, Christina A1 - Schmidt, Burkard A1 - Blaser, Rainer A1 - Kremer, Marcus A1 - Peschel, Christian A1 - Germing, Ulrich A1 - Platzbecker, Uwe A1 - Goetze, Katharina T1 - Response to azacitidine is independent of p53 expression in higher-risk myelodysplastic syndromes and secondary acute myeloid leukemia JF - HAEMATOLOGICA N2 - No abstract available. KW - TP53 mutations KW - DEL(5Q) KW - MDS KW - p53 expression KW - azacitidine KW - scoring system KW - prognosis KW - karyotype Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-115313 SN - 1592-8721 VL - 99 IS - 10 ER - TY - JOUR A1 - Gewies, Andreas A1 - Gorka, Oliver A1 - Bergmann, Hanna A1 - Pechloff, Konstanze A1 - Petermann, Franziska A1 - Jeltsch, Katharina M. A1 - Rudelius, Martina A1 - Kriegsmann, Mark A1 - Weichert, Wilko A1 - Horsch, Marion A1 - Beckers, Johannes A1 - Wurst, Wolfgang A1 - Heikenwalder, Mathias A1 - Korn, Thomas A1 - Heissmeyer, Vigo A1 - Ruland, Juergen T1 - Uncoupling Malt1 Threshold Function from Paracaspase Activity Results in Destructive Autoimmune Inflammation JF - Cell Reports N2 - The paracaspase Malt1 is a central regulator of antigen receptor signaling that is frequently mutated in human lymphoma. As a scaffold, it assembles protein complexes for NF-kappa B activation, and its proteolytic domain cleaves negative NF-kappa B regulators for signal enforcement. Still, the physiological functions of Malt1-protease are unknown. We demonstrate that targeted Malt1-paracaspase inactivation induces a lethal inflammatory syndrome with lymphocyte-dependent neurodegeneration in vivo. Paracaspase activity is essential for regulatory T cell (Treg) and innate-like B cell development, but it is largely dispensable for overcoming Malt1-dependent thresholds for lymphocyte activation. In addition to NF-kappa B inhibitors, Malt1 cleaves an entire set of mRNA stability regulators, including Roquin-1, Roquin-2, and Regnase-1, and paracaspase inactivation results in excessive interferon gamma (IFN gamma) production by effector lymphocytes that drive pathology. Together, our results reveal distinct threshold and modulatory functions of Malt1 that differentially control lymphocyte differentiation and activation pathways and demonstrate that selective paracaspase blockage skews systemic immunity toward destructive autoinflammation. KW - helper T-cells KW - combined immunodeficiency KW - messenger RNA KW - roquin KW - mice KW - NF-KAPPA-B KW - lymphoid-tissue KW - activation KW - cleavage KW - mutations Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114627 VL - 9 IS - 4 ER - TY - JOUR A1 - Wester, Hans Jürgen A1 - Keller, Ulrich A1 - Schottelius, Margret A1 - Beer, Ambros A1 - Philipp-Abbrederis, Kathrin A1 - Hoffmann, Frauke A1 - Šimeček, Jakub A1 - Gerngross, Carlos A1 - Lassmann, Michael A1 - Herrmann, Ken A1 - Pellegata, Natalia A1 - Rudelius, Martina A1 - Kessler, Horst A1 - Schwaiger, Markus T1 - Disclosing the CXCR4 expression in lymphoproliferative diseases by targeted molecular imaging JF - Theranostics N2 - Chemokine ligand-receptor interactions play a pivotal role in cell attraction and cellular trafficking, both in normal tissue homeostasis and in disease. In cancer, chemokine receptor-4 (CXCR4) expression is an adverse prognostic factor. Early clinical studies suggest that targeting CXCR4 with suitable high-affinity antagonists might be a novel means for therapy. In addition to the preclinical evaluation of [\(^{68}\)Ga]Pentixafor in mice bearing human lymphoma xenografts as an exemplary CXCR4-expressing tumor entity, we report on the first clinical applications of [\(^{68}\)Ga]Pentixafor-Positron Emission Tomography as a powerful method for CXCR4 imaging in cancer patients. [\(^{68}\)Ga]Pentixafor binds with high affinity and selectivity to human CXCR4 and exhibits a favorable dosimetry. [\(^{68}\)Ga]Pentixafor-PET provides images with excellent specificity and contrast. This non-invasive imaging technology for quantitative assessment of CXCR4 expression allows to further elucidate the role of CXCR4/CXCL12 ligand interaction in the pathogenesis and treatment of cancer, cardiovascular diseases and autoimmune and inflammatory disorders. KW - acute myeloid leukemia KW - prognostic value KW - therapeutic target KW - chemokine receptor KW - CXCR4 KW - lymphoma KW - in vivo imaging KW - positron emission tomography Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144537 VL - 5 IS - 6 ER - TY - JOUR A1 - Philipp-Abbrederis, Kathrin A1 - Herrmann, Ken A1 - Knop, Stefan A1 - Schottelius, Margret A1 - Eiber, Matthias A1 - Lückerath, Katharina A1 - Pietschmann, Elke A1 - Habringer, Stefan A1 - Gerngroß, Carlos A1 - Franke, Katharina A1 - Rudelius, Martina A1 - Schirbel, Andreas A1 - Lapa, Constantin A1 - Schwamborn, Kristina A1 - Steidle, Sabine A1 - Hartmann, Elena A1 - Rosenwald, Andreas A1 - Kropf, Saskia A1 - Beer, Ambros J A1 - Peschel, Christian A1 - Einsele, Hermann A1 - Buck, Andreas K A1 - Schwaiger, Markus A1 - Götze, Katharina A1 - Wester, Hans-Jürgen A1 - Keller, Ulrich T1 - In vivo molecular imaging of chemokine receptor CXCR4 expression in patients with advanced multiple myeloma JF - EMBO Molecular Medicine N2 - CXCR4 is a G-protein-coupled receptor that mediates recruitment of blood cells toward its ligand SDF-1. In cancer, high CXCR4 expression is frequently associated with tumor dissemination andpoor prognosis. We evaluated the novel CXCR4 probe [\(^{68}\)Ga]Pentixafor for invivo mapping of CXCR4 expression density in mice xenografted with human CXCR4-positive MM cell lines and patients with advanced MM by means of positron emission tomography (PET). [\(^{68}\)Ga]Pentixafor PET provided images with excellent specificity and contrast. In 10 of 14 patients with advanced MM [\(^{68}\)Ga]Pentixafor PET/CT scans revealed MM manifestations, whereas only nine of 14 standard [\(^{18}\)F]fluorodeoxyglucose PET/CT scans were rated visually positive. Assessment of blood counts and standard CD34\(^{+}\) flow cytometry did not reveal significant blood count changes associated with tracer application. Based on these highly encouraging data on clinical PET imaging of CXCR4 expression in a cohort of MM patients, we conclude that [\(^{68}\)Ga]Pentixafor PET opens a broad field for clinical investigations on CXCR4 expression and for CXCR4-directed therapeutic approaches in MM and other diseases. KW - FDG PET/CT KW - cells KW - CXCR4/SDF-1 KW - CXCR4 KW - multiple myeloma KW - positron emission tomography KW - chemokine receptor KW - in vivo imaging KW - malignancies KW - involvement KW - microenvironment KW - survival KW - cancer KW - autologous transplantation KW - bone disease Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148738 VL - 7 IS - 4 ER - TY - JOUR A1 - Lapa, Constantin A1 - Lückerath, Katharina A1 - Kleinlein, Irene A1 - Monoranu, Camelia Maria A1 - Linsenmann, Thomas A1 - Kessler, Almuth F. A1 - Rudelius, Martina A1 - Kropf, Saskia A1 - Buck, Andreas K. A1 - Ernestus, Ralf-Ingo A1 - Wester, Hans-Jürgen A1 - Löhr, Mario A1 - Herrmann, Ken T1 - \(^{68}\)Ga-Pentixafor-PET/CT for Imaging of Chemokine Receptor 4 Expression in Glioblastoma JF - Theranostics N2 - Chemokine receptor-4 (CXCR4) has been reported to be overexpressed in glioblastoma (GBM) and to be associated with poor survival. This study investigated the feasibility of non-invasive CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using the radiolabelled chemokine receptor ligand \(^{68}\)Ga-Pentixafor. 15 patients with clinical suspicion on primary or recurrent glioblastoma (13 primary, 2 recurrent tumors) underwent \(^{68}\)Ga-Pentixafor-PET/CT for assessment of CXCR4 expression prior to surgery. O-(2-\(^{18}\)F-fluoroethyl)-L-tyrosine (\(^{18}\)F-FET) PET/CT images were available in 11/15 cases and were compared visually and semi-quantitatively (SUV\(_{max}\), SUV\(_{mean}\)). Tumor-to-background ratios (TBR) were calculated for both PET probes. \(^{68}\)Ga-Pentixafor-PET/CT results were also compared to histological CXCR4 expression on neuronavigated surgical samples. \(^{68}\)Ga-Pentixafor-PET/CT was visually positive in 13/15 cases with SUV\(_{mean}\) and SUV\(_{max}\) of 3.0±1.5 and 3.9±2.0 respectively. Respective values for \(^{18}\)F-FET were 4.4±2.0 (SUV\(_{mean}\)) and 5.3±2.3 (SUV\(_{max}\)). TBR for SUV\(_{mean}\) and SUV\(_{max}\) were higher for \(^{68}\)Ga-Pentixafor than for \(^{18}\)F-FET (SUV\(_{mean}\) 154.0±90.7 vs. 4.1±1.3; SUV\(_{max}\) 70.3±44.0 and 3.8±1.2, p<0.01), respectively. Histological analysis confirmed CXCR4 expression in tumor areas with high \(^{68}\)Ga-Pentixafor uptake; regions of the same tumor without apparent \(^{68}\)Ga-Pentixafor uptake showed no or low receptor expression. In this pilot study, \(^{68}\)Ga-Pentixafor retention has been observed in the vast majority of glioblastoma lesions and served as readout for non-invasive determination of CXCR4 expression. Given the paramount importance of the CXCR4/SDF-1 axis in tumor biology, \(^{68}\)Ga-Pentixafor-PET/CT might prove a useful tool for sensitive, non-invasive in-vivo quantification of CXCR4 as well as selection of patients who might benefit from CXCR4-directed therapy. KW - imaging KW - chemokine receptor-4 KW - glioblastoma KW - positron emission tomography/computed tomography KW - \(^{68}\)Ga-Pentixafor Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168174 VL - 6 IS - 3 ER - TY - JOUR A1 - Engel, Katharina A1 - Rudelius, Martina A1 - Slawska, Jolanta A1 - Jacobs, Laura A1 - Abhari, Behnaz Ahangarian A1 - Altmann, Bettina A1 - Kurutz, Julia A1 - Rathakrishnan, Abirami A1 - Fernández-Sáiz, Vanesa A1 - Brunner, Andrä A1 - Targosz, Bianca-Sabrina A1 - Loewecke, Felicia A1 - Gloeckner, Christian Johannes A1 - Ueffing, Marius A1 - Fulda, Simone A1 - Pfreundschuh, Michael A1 - Trümper, Lorenz A1 - Klapper, Wolfram A1 - Keller, Ulrich A1 - Jost, Philipp J. A1 - Rosenwald, Andreas A1 - Peschel, Christian A1 - Bassermann, Florian T1 - USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B-cell lymphoma JF - EMBO Molecular Medicine N2 - 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. We show that high USP9X/XIAP expression is associated with shorter event‐free survival in patients treated with spindle poison‐containing chemotherapy. Accordingly, aggressive B‐cell lymphoma lines with USP9X and associated XIAP overexpression exhibit increased chemoresistance, reversed by specific inhibition of either USP9X or XIAP. Moreover, knockdown of USP9X or XIAP significantly delays lymphoma development and increases sensitivity to spindle poisons in a murine Eμ‐Myc lymphoma model. Together, we specify the USP9X–XIAP axis as a regulator of the mitotic cell fate decision and propose that USP9X and XIAP are potential prognostic biomarkers and therapeutic targets in aggressive B‐cell lymphoma. KW - B‐cell lymphoma KW - mitosis KW - ubiquitin KW - USP9X KW - XIAP Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165016 VL - 8 ER - TY - JOUR A1 - Rauert-Wunderlich, Hilka A1 - Berberich, Ingolf A1 - Rosenwald, Andreas A1 - Rudelius, Martina T1 - CD40L mediated alternative NF kappa B-signaling induces resistance to BCR-inhibitors in patients with mantle cell lymphoma JF - Cell Death & Disease N2 - Drug resistance is a significant obstacle in cancer treatment and therefore a frequent subject of research. Developed or primary resistance limits the treatment success of inhibitors of the B cell receptor (BCR) pathway in mantle cell lymphoma (MCL) patients. Recent research has highlighted the role of the nuclear factor-kappa B (NF kappa B) pathway in the context of resistance to BCR inhibitors in MCL. In this study, we analyzed the dependency of MCL cell lines on NF kappa B signaling and illustrated the ability of CD40L to activate the alternative NF kappa B pathway in MCL. This activation leads to independency of classical NF kappa B signaling and results in resistance to BCR inhibitors. Therefore, ligands (such as CD40L) and their activation of the alternative NF kappa B pathway have a major impact on the drug response in MCL. Furthermore, this study indicates a protective role for cells expressing specific ligands as microenvironmental niches for MCL cells and underlines the significance of therapeutically targeting alternative NF kappa B signaling in MCL. KW - Bruton Tyrosine Kinase KW - Tumor Microenvironment KW - Targeted Therapies KW - Ibrutinib KW - Pathway KW - Malignancies KW - Activation KW - Ligand KW - Proliferation KW - PCI-32765 Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225027 IS - 9 ER - TY - JOUR A1 - Rudelius, Martina A1 - Rosenfeldt, Mathias Tillmann A1 - Leich, Ellen A1 - Rauert-Wunderlich, Hilka A1 - Solimando, Antonio Giovanni A1 - Ott, German A1 - Rosenwald, Andreas A1 - Beilhack, Andreas T1 - Inhibition of focal adhesion kinase overcomes resistance of mantle cell lymphoma to ibrutinib in the bone marrow microenvironment JF - Haematologica N2 - Mantle cell lymphoma and other lymphoma subtypes often spread to the bone marrow, and stromal interactions mediated by focal adhesion kinase frequently enhance survival and drug resistance of the lymphoma cells. To study the role of focal adhesion kinase in mantle cell lymphoma, immunohistochemistry of primary cases and functional analysis of mantle cell lymphoma cell lines and primary mantle cell lymphoma cells co-cultured with bone marrow stromal cells (BMSC) using small molecule inhibitors and RNAi-based focal adhesion kinase silencing was performed. We showed that focal adhesion kinase is highly expressed in bone marrow infiltrates of mantle cell lymphoma and in mantle cell lymphoma cell lines. Stroma-mediated activation of focal adhesion kinase led to activation of multiple kinases (AKT, p42/44 and NF-kappa B), that are important for prosurvival and proliferation signaling. Interestingly, RNAi-based focal adhesion kinase silencing or inhibition with small molecule inhibitors (FAKi) resulted in blockage of targeted cell invasion and induced apoptosis by inactivation of multiple signaling cascades, including the classic and alternative NF-kappa B pathway. In addition, the combined treatment of ibrutinib and FAKi was highly synergistic, and ibrutinib resistance of mantle cell lymphoma could be overcome. These data demonstrate that focal adhesion kinase is important for stroma-mediated survival and drug resistance in mantle cell lymphoma, providing indications for a targeted therapeutic strategy. KW - NF-Kappa-B KW - Stromal cells KW - Induced apoptosis KW - Fak regulation KW - Phase- KW - Multiple KW - Activation KW - Mechanisms KW - Migration KW - Pathogenesis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227117 VL - 103 IS - 1 ER -