@article{SchuemannGrossBaueretal.2021, author = {Sch{\"u}mann, Franziska Lea and Groß, Elisabeth and Bauer, Marcus and Rohde, Christian and Sandmann, Sarah and Terziev, Denis and M{\"u}ller, Lutz P. and Posern, Guido and Wienke, Andreas and Fend, Falko and Hansmann, Martin-Leo and Klapper, Wolfram and Rosenwald, Andreas and Stein, Harald and Dugas, Martin and M{\"u}ller-Tidow, Carsten and Wickenhauser, Claudia and Binder, Mascha and Weber, Thomas}, title = {Divergent effects of EZH1 and EZH2 protein expression on the prognosis of patients with T-cell lymphomas}, series = {Biomedicines}, volume = {9}, journal = {Biomedicines}, number = {12}, issn = {2227-9059}, doi = {10.3390/biomedicines9121842}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252155}, year = {2021}, abstract = {T-cell lymphomas are highly heterogeneous and their prognosis is poor under the currently available therapies. Enhancers of zeste homologue 1 and 2 (EZH1/2) are histone H3 lysine-27 trimethyltransferases (H3K27me3). Despite the rapid development of new drugs inhibiting EZH2 and/or EZH1, the molecular interplay of these proteins and the impact on disease progression and prognosis of patients with T-cell lymphomas remains insufficiently understood. In this study, EZH1/2 mutation status was evaluated in 33 monomorphic epitheliotropic intestinal T-cell lymphomas by next generation sequencing and EZH1/2 and H3K27me3 protein expression levels were detected by immunohistochemistry in 46 T-cell lymphomas. Correlations with clinicopathologic features were analyzed and survival curves generated. No EZH1 mutations and one (3\%) EZH2 missense mutation were identified. In univariable analysis, high EZH1 expression was associated with an improved overall survival (OS) and progression-free survival (PFS) whereas high EZH2 and H3K27me3 expression were associated with poorer OS and PFS. Multivariable analysis revealed EZH1 (hazard ratio (HR) = 0.183; 95\% confidence interval (CI): 0.044-0.767; p = 0.020;) and EZH2 (HR = 8.245; 95\% CI: 1.898-35.826; p = 0.005) to be independent, divergent prognostic markers for OS. In conclusion, EZH1/2 protein expression had opposing effects on the prognosis of T-cell lymphoma patients.}, language = {en} } @article{TonyBurmesterSchulzeKoopsetal.2011, author = {Tony, Hans-Peter and Burmester, Gerd and Schulze-Koops, Hendrik and Grunke, Mathias and Henes, Joerg and K{\"o}tter, Ina and Haas, Judith and Unger, Leonore and Lovric, Svjetlana and Haubitz, Marion and Fischer-Betz, Rebecca and Chehab, Gamal and Rubbert-Roth, Andrea and Specker, Christof and Weinerth, Jutta and Holle, Julia and M{\"u}ller-Ladner, Ulf and K{\"o}nig, Ramona and Fiehn, Christoph and Burgwinkel, Philip and Budde, Klemens and S{\"o}rensen, Helmut and Meurer, Michael and Aringer, Martin and Kieseier, Bernd and Erfurt-Berge, Cornelia and Sticherling, Michael and Veelken, Roland and Ziemann, Ulf and Strutz, Frank and von Wussow, Praxis and Meier, Florian MP and Hunzelmann, Nico and Schmidt, Enno and Bergner, Raoul and Schwarting, Andreas and Eming, R{\"u}diger and Schwarz-Eywill, Michael and Wassenberg, Siegfried and Fleck, Martin and Metzler, Claudia and Zettl, Uwe and Westphal, Jens and Heitmann, Stefan and Herzog, Anna L. and Wiendl, Heinz and Jakob, Waltraud and Schmidt, Elvira and Freivogel, Klaus and D{\"o}rner, Thomas and Hertl, Michael and Stadler, Rudolf}, title = {Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID)}, series = {Arthritis Research \& Therapy}, volume = {13}, journal = {Arthritis Research \& Therapy}, number = {R75}, doi = {10.1186/ar3337}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142856}, pages = {1-14}, year = {2011}, abstract = {Introduction: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting. Methods: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators. Results: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0\% with systemic lupus erythematosus, 15.7\% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1\% multiple sclerosis and 10.0\% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0\% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3\% of patients showed no response, 45.1\% showed a partial response and 41.6\% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm)}, language = {en} } @article{HoubenHesbacherSchmidetal.2011, author = {Houben, Roland and Hesbacher, Sonja and Schmid, Corinna P. and Kauczok, Claudia S. and Flohr, Ulrike and Haferkamp, Sebastian and M{\"u}ller, Cornelia S. L. and Schrama, David and Wischhusen, J{\"o}rg and Becker, J{\"u}rgen C.}, title = {High-Level Expression of Wild-Type p53 in Melanoma Cells is Frequently Associated with Inactivity in p53 Reporter Gene Assays}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-69012}, year = {2011}, abstract = {Background: Inactivation of the p53 pathway that controls cell cycle progression, apoptosis and senescence, has been proposed to occur in virtually all human tumors and p53 is the protein most frequently mutated in human cancer. However, the mutational status of p53 in melanoma is still controversial; to clarify this notion we analysed the largest series of melanoma samples reported to date. Methodology/Principal Findings: Immunohistochemical analysis of more than 180 melanoma specimens demonstrated that high levels of p53 are expressed in the vast majority of cases. Subsequent sequencing of the p53 exons 5-8, however, revealed only in one case the presence of a mutation. Nevertheless, by means of two different p53 reporter constructs we demonstrate transcriptional inactivity of wild type p53 in 6 out of 10 melanoma cell lines; the 4 other p53 wild type melanoma cell lines exhibit p53 reporter gene activity, which can be blocked by shRNA knock down of p53. Conclusions/Significance: In melanomas expressing high levels of wild type p53 this tumor suppressor is frequently inactivated at transcriptional level.}, subject = {Krebs }, language = {en} } @article{ChatterjeeAndrulisStuehmeretal.2013, author = {Chatterjee, Manik and Andrulis, Mindaugas and St{\"u}hmer, Thorsten and M{\"u}ller, Elisabeth and Hofmann, Claudia and Steinbrunn, Torsten and Heimberger, Tanja and Schraud, Heike and Kressmann, Stefanie and Einsele, Hermann and Bargou, Ralf C.}, title = {The PI3K/Akt signaling pathway regulates the expression of Hsp70, which critically contributes to Hsp90-chaperone function and tumor cell survival in multiple myeloma}, series = {Haematologica}, volume = {98}, journal = {Haematologica}, number = {7}, doi = {10.3324/haematol.2012.066175}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130574}, pages = {1132-1141}, year = {2013}, abstract = {Despite therapeutic advances multiple myeloma remains largely incurable, and novel therapeutic concepts are needed. The Hsp90-chaperone is a reasonable therapeutic target, because it maintains oncogenic signaling of multiple deregulated pathways. However, in contrast to promising pre-clinical results, only limited clinical efficacy has been achieved through pharmacological Hsp90 inhibition. Because Hsp70 has been described to interact functionally with the Hsp90-complex, we analyzed the suitability of Hsp72 and Hsp73 as potential additional target sites. Expression of Hsp72 and Hsp73 in myeloma cells was analyzed by immunohistochemical staining and western blotting. Short interfering RNA-mediated knockdown or pharmacological inhibition of Hsp72 and Hsp73 was performed to evaluate the role of these proteins in myeloma cell survival and for Hsp90-chaperone function. Furthermore, the role of PI3K-dependent signaling in constitutive and inducible Hsp70 expression was investigated using short interfering RNA-mediated and pharmacological PI3K inhibition. Hsp72 and Hsp73 were frequently overexpressed in multiple myeloma. Knockdown of Hsp72 and/or Hsp73 or treatment with VER-155008 induced apoptosis of myeloma cells. Hsp72/Hsp73 inhibition decreased protein levels of Hsp90-chaperone clients affecting multiple oncogenic signaling pathways, and acted synergistically with the Hsp90 inhibitor NVP-AUY922 in the induction of death of myeloma cells. Inhibition of the PI3K/Akt/GSK3b pathway with short interfering RNA or PI103 decreased expression of the heat shock transcription factor 1 and down-regulated constitutive and inducible Hsp70 expression. Treatment of myeloma cells with a combination of NVP-AUY922 and PI103 resulted in additive to synergistic cytotoxicity. In conclusion, Hsp72 and Hsp73 sustain Hsp90-haperone function and critically contribute to the survival of myeloma cells. Translation of Hsp70 inhibition into the clinic is therefore highly desirable. Treatment with PI3K inhibitors might represent an alternative therapeutic strategy to target Hsp70.}, language = {en} } @article{HanfsteinLausekerHehlmannetal.2014, author = {Hanfstein, Benjamin and Lauseker, Michael and Hehlmann, R{\"u}diger and Saussele, Susanne and Erben, Philipp and Dietz, Christian and Fabarius, Alice and Proetel, Ulrike and Schnittger, Susanne and Haferlach, Claudia and Krause, Stefan W. and Schubert, J{\"o}rg and Einsele, Hermann and H{\"a}nel, Mathias and Dengler, Jolanta and Falge, Christiane and Kanz, Lothar and Neubauer, Andreas and Kneba, Michael and Stengelmann, Frank and Pfreundschuh, Michael and Waller, Cornelius F. and Spiekerman, Karsten and Baerlocher, Gabriela M. and Pfirrmann, Markus and Hasford, Joerg and Hofmann, Wolf-Karsten and Hochhaus, Andreas and M{\"u}ller, Martin C.}, title = {Distinct characteristics of e13a2 versus e14a2 BCR-ABL1 driven chronic myeloid leukemia under first-line therapy with imatinib}, series = {Haematologica}, volume = {99}, journal = {Haematologica}, number = {9}, issn = {1592-8721}, doi = {10.3324/haematol.2013.096537}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115476}, pages = {1441-1447}, year = {2014}, abstract = {The vast majority of chronic myeloid leukemia patients express a BCR-ABL1 fusion gene mRNA encoding a 210 kDa tyrosine kinase which promotes leukemic transformation. A possible differential impact of the corresponding BCR-ABL1 transcript variants e13a2 ("b2a2") and e14a2 ("b3a2") on disease phenotype and outcome is still a subject of debate. A total of 1105 newly diagnosed imatinib-treated patients were analyzed according to transcript type at diagnosis (e13a2, n=451; e14a2, n=496; e13a2+e14a2, n=158). No differences regarding age, sex, or Euro risk score were observed. A significant difference was found between e13a2 and e14a2 when comparing white blood cells (88 vs. 65 x 10(9)/L, respectively; P<0.001) and platelets (296 vs. 430 x 109/L, respectively; P<0.001) at diagnosis, indicating a distinct disease phenotype. No significant difference was observed regarding other hematologic features, including spleen size and hematologic adverse events, during imatinib-based therapies. Cumulative molecular response was inferior in e13a2 patients (P=0.002 for major molecular response; P<0.001 for MR4). No difference was observed with regard to cytogenetic response and overall survival. In conclusion, e13a2 and e14a2 chronic myeloid leukemia seem to represent distinct biological entities. However, clinical outcome under imatinib treatment was comparable and no risk prediction can be made according to e13a2 versus e14a2 BCR-ABL1 transcript type at diagnosis. (clinicaltrials.gov identifier: 00055874)}, language = {en} } @phdthesis{Mueller2005, author = {M{\"u}ller, Claudia Maria}, title = {Studies on the Role of Histone-like Proteins in Gene Regulation in Uropathogenic Escherichia coli Isolate 536}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-17617}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2005}, abstract = {In this study, the role of histone-like proteins in gene regulation in uropathogenic Escherichia coli isolate 536 was monitored. The histone-like nucleoid structuring protein H-NS is a global regulator in Escherichia coli that has been intensively studied in non-pathogenic strains. No comprehensive study on the role of H-NS and it's homolog StpA on gene expression in a pathogenic E. coli strain has been carried out so far. Moreover, we identified a third, so far uncharacterized member of the H-NS-like protein family in uropathogenic E. coli isolate 536, which was designated Hlp (H-NS-like protein). Hlp is a 134-amino acid protein, which shares 58 \% sequence identity with H-NS. The gene coding for the Hlp protein, hlp, is found in several uropathogenic E. coli variants, but not in non-pathogenic E. coli K-12. In UPEC strains 536 and CFT073, Hlp is encoded on a possibly horizontally acquired 23-kb genomic region inserted into the serU locus. Studies on hlp transcription revealed, that the gene is transcribed monocistronically from a single promoter and that expression is repressed by H-NS. Purified Hlp protein was binding to its own and to the hns promoter, thereby mediating negative auto- and crossregulation. Furthermore, Hlp and H-NS were directly interacting, resulting in the formation of stable heteromers. Complementation studies with hns mutant strains in a K-12 background revealed that the Hlp protein had in vivo activity, being able to complement the lack of H-NS in terms of motility, growth, and repression of the proU, bgl, and clyA genes. When analyzing the role of the histone-like proteins in expression of virulence-associated genes by using DNA arrays and classical phenotypic assays, most of the observed effects were mediated by the H-NS protein alone. Expression profiling revealed that transcript level of more than 500 genes was affected by an hns mutation, resulting in increased expression of alpha-hemolysin, fimbriae and iron-uptake systems, as well as genes involved in stress adaptation. Furthermore, several other putative virulence factors were found to be part of the H-NS regulon. On the other hand, no effect of StpA alone was observed. An hns stpA double mutant, however, exhibited a distinct gene expression pattern that differed in great parts from that of the hns single mutant. This suggests a direct interaction between the two homologs and the existence of distinct regulons of H-NS and an H-NS/StpA heteromeric complex. Although the H-NS protein has - either as homomer or in complex with StpA - a marked impact on gene expression in pathogenic E. coli strains, its effect on urovirulence is ambiguous. At a high infection dose, hns mutants accelerate lethality in murine UTI and sepsis models relative to the wild type, probably due to increased production of alpha-hemolysin. At lower infectious dose, however, mutants lacking H-NS are attenuated through their impaired growth rate, which can only partially be compensated by the higher expression of numerous virulence factors. As seen with StpA, an hlp single mutant did not exhibit a notable phenotype under standard growth conditions. A severe growth defect of hns hlp double mutants at low temperatures, however, suggests a biological relevance of H-NS/Hlp heteromers under certain circumstances. Furthermore, these mutants expressed more capsular polysaccharide and curli fimbriae, thereby indicating a distinct role of H-NS and Hlp in regulation of these surface structures. The H-NS paralogs Hlp and StpA also modulated H-NS-mediated regulation of fimbrial adhesins, and are oppositely required for normal growth at low or high temperatures, respectively. Finally, expression levels of the three histone-like proteins H-NS, StpA and Hlp itself varied with different temperatures, thereby suggesting a flexible composition of the nucleoid-associated protein pool. Hence, we propose that the biological role of Hlp and StpA does not rely on a distinct function of the single protein, but rather on their interaction with the global regulator H-NS.}, subject = {Escherichia coli}, language = {en} } @techreport{MuellerSchererLorenzenAmmeretal.2022, author = {M{\"u}ller, J{\"o}rg and Scherer-Lorenzen, Michael and Ammer, Christian and Eisenhauer, Nico and Seidel, Dominik and Schuldt, Bernhard and Biedermann, Peter and Schmitt, Thomas and K{\"u}nzer, Claudia and Wegmann, Martin and Cesarz, Simone and Peters, Marcell and Feldhaar, Heike and Steffan-Dewenter, Ingolf and Claßen, Alice and B{\"a}ssler, Claus and von Oheimb, Goddert and Fichtner, Andreas and Thorn, Simon and Weisser, Wolfgang}, title = {BETA-FOR: Erh{\"o}hung der strukturellen Diversit{\"a}t zwischen Waldbest{\"a}nden zur Erh{\"o}hung der Multidiversit{\"a}t und Multifunktionalit{\"a}t in Produktionsw{\"a}ldern. Antragstext f{\"u}r die DFG Forschungsgruppe FOR 5375}, doi = {10.25972/OPUS-29084}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-290849}, pages = {210}, year = {2022}, abstract = {Der in j{\"u}ngster Zeit beobachtete kontinuierliche Verlust der β-Diversit{\"a}t in {\"O}kosystemen deutet auf homogene Gemeinschaften auf Landschaftsebene hin, was haupts{\"a}chlich auf die steigende Landnutzungsintensit{\"a}t zur{\"u}ckgef{\"u}hrt wird. Biologische Vielfalt ist mit zahlreichen Funktionen und der Stabilit{\"a}t von {\"O}kosystemen verkn{\"u}pft. Es ist daher zu erwarten, dass eine abnehmende β-Diversit{\"a}t auch die Multifunktionalit{\"a}t verringert. Wir kombinieren hier Fachwissen aus der Forstwissenschaft, der {\"O}kologie, der Fernerkundung, der chemischen {\"O}kologie und der Statistik in einem gemeinschaftlichen und experimentellen β-Diversit{\"a}tsdesign, um einerseits die Auswirkungen der Homogenisierung zu bewerten und andererseits Konzepte zu entwickeln, um negative Auswirkungen durch Homogenisierung in W{\"a}ldern r{\"u}ckg{\"a}ngig zu machen. Konkret werden wir uns mit der Frage besch{\"a}ftigen, ob die Verbesserung der strukturellen β-Komplexit{\"a}t (ESBC) in W{\"a}ldern durch Waldbau oder nat{\"u}rliche St{\"o}rungen die Biodiversit{\"a}t und Multifunktionalit{\"a}t in ehemals homogenen Produktionsw{\"a}ldern erh{\"o}hen kann. Unser Ansatz wird m{\"o}gliche Mechanismen hinter den beobachteten Homogenisierungs-Diversit{\"a}ts-Beziehungen identifizieren und zeigen, wie sich diese auf die Multifunktionalit{\"a}t auswirken. An elf Standorten in ganz Deutschland haben wir dazu zwei Waldbest{\"a}nde als zwei kleine "Waldlandschaften" ausgew{\"a}hlt. In einem dieser beiden Best{\"a}nde haben wir ESBC (Enhancement of Structural Beta Complexity)-Behandlungen durchgef{\"u}hrt. Im zweiten, dem Kontrollbestand, werden wir die gleich Anzahl 50x50m Parzellen ohne ESBC einrichten. Auf allen Parzellen werden wir 18 taxonomische Artengruppen aller trophischer Ebenen und 21 {\"O}kosystemfunktionen, einschließlich der wichtigsten Funktionen in W{\"a}ldern der gem{\"a}ßigten Zonen, messen. Der statistische Rahmen wird eine umfassende Analyse der Biodiversit{\"a}t erm{\"o}glichen, indem verschiedenen Aspekte (taxonomische, funktionelle und phylogenetische Vielfalt) auf verschiedenen Skalenebenen (α-, β-, γ-Diversit{\"a}t) quantifiziert werden. Um die Gesamtdiversit{\"a}t zu kombinieren, werden wir das Konzept der Multidiversit{\"a}t auf die 18 Taxa anwenden. Wir werden neue Ans{\"a}tze zur Quantifizierung und Aufteilung der Multifunktionalit{\"a}t auf α- und β-Skalen verwenden und entwickeln. Durch die experimentelle Beschreibung des Zusammenhangs zwischen β-Diversit{\"a}t und Multifunktionalit{\"a}t in einer Reallandschaft wird unsere Forschung einen neuen Weg einschlagen. Dar{\"u}ber hinaus werden wir dazu beitragen, verbesserte Leitlinien f{\"u}r waldbauliche Konzepte und f{\"u}r das Management nat{\"u}rlicher St{\"o}rungen zu entwickeln, um Homogenisierungseffekte der Vergangenheit umzukehren.}, subject = {Wald{\"o}kosystem}, language = {en} } @article{MuellerGirardHopfneretal.2016, author = {M{\"u}ller, Stefanie H. and Girard, Simon L. and Hopfner, Franziska and Merner, Nancy D. and Bourassa, Cynthia V. and Lorenz, Delia and Clark, Lorraine N. and Tittmann, Lukas and Soto-Ortolaza, Alexandra I. and Klebe, Stephan and Hallett, Mark and Schneider, Susanne A. and Hodgkinson, Colin A. and Lieb, Wolfgang and Wszolek, Zbigniew K. and Pendziwiat, Manuela and Lorenzo-Betancor, Oswaldo and Poewe, Werner and Ortega-Cubero, Sara and Seppi, Klaus and Rajput, Alex and Hussl, Anna and Rajput, Ali H. and Berg, Daniela and Dion, Patrick A. and Wurster, Isabel and Shulman, Joshua M. and Srulijes, Karin and Haubenberger, Dietrich and Pastor, Pau and Vilari{\~n}o-G{\"u}ell, Carles and Postuma, Ronald B. and Bernard, Genevi{\`e}ve and Ladwig, Karl-Heinz and Dupr{\´e}, Nicolas and Jankovic, Joseph and Strauch, Konstantin and Panisset, Michel and Winkelmann, Juliane and Testa, Claudia M. and Reischl, Eva and Zeuner, Kirsten E. and Ross, Owen A. and Arzberger, Thomas and Chouinard, Sylvain and Deuschl, G{\"u}nther and Louis, Elan D. and Kuhlenb{\"a}umer, Gregor and Rouleau, Guy A.}, title = {Genome-wide association study in essential tremor identifies three new loci}, series = {Brain}, volume = {139}, journal = {Brain}, doi = {10.1093/brain/aww242}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-186541}, pages = {3163-3169}, year = {2016}, abstract = {We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.}, language = {en} } @article{BerntRangrezEdenetal.2016, author = {Bernt, Alexander and Rangrez, Ashraf Y. and Eden, Matthias and Jungmann, Andreas and Katz, Sylvia and Rohr, Claudia and M{\"u}ller, Oliver J. and Katus, Hugo A. and Sossalla, Samuel T. and Williams, Tatjana and Ritter, Oliver and Frank, Derk and Frey, Norbert}, title = {Sumoylation-independent activation of Calcineurin-NFAT-signaling via SUMO2 mediates cardiomyocyte hypertrophy}, series = {Scientific Reports}, volume = {6}, journal = {Scientific Reports}, number = {35758}, doi = {10.1038/srep35758}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-167525}, year = {2016}, abstract = {The objective of this study was to identify unknown modulators of Calcineurin (Cn)-NFAT signaling. Measurement of NFAT reporter driven luciferase activity was therefore utilized to screen a human cardiac cDNA-library (~10\(^{7}\) primary clones) in C2C12 cells through serial dilutions until single clones could be identified. This extensive screening strategy culminated in the identification of SUMO2 as a most efficient Cn-NFAT activator. SUMO2-mediated activation of Cn-NFAT signaling in cardiomyocytes translated into a hypertrophic phenotype. Prohypertrophic effects were also observed in mice expressing SUMO2 in the heart using AAV9 (Adeno-associated virus), complementing the in vitro findings. In addition, increased SUMO2-mediated sumoylation in human cardiomyopathy patients and in mouse models of cardiomyopathy were observed. To decipher the underlying mechanism, we generated a sumoylation-deficient SUMO2 mutant (ΔGG). Surprisingly, ΔGG replicated Cn-NFAT-activation and the prohypertrophic effects of native SUMO2, both in vitro and in vivo, suggesting a sumoylation-independent mechanism. Finally, we discerned a direct interaction between SUMO2 and CnA, which promotes CnA nuclear localization. In conclusion, we identified SUMO2 as a novel activator of Cn-NFAT signaling in cardiomyocytes. In broader terms, these findings reveal an unexpected role for SUMO2 in cardiac hypertrophy and cardiomyopathy, which may open the possibility for therapeutic manipulation of this pathway.}, language = {en} } @article{EckardtStasikKrameretal.2021, author = {Eckardt, Jan-Niklas and Stasik, Sebastian and Kramer, Michael and R{\"o}llig, Christoph and Kr{\"a}mer, Alwin and Scholl, Sebastian and Hochhaus, Andreas and Crysandt, Martina and Br{\"u}mmendorf, Tim H. and Naumann, Ralph and Steffen, Bj{\"o}rn and Kunzmann, Volker and Einsele, Hermann and Schaich, Markus and Burchert, Andreas and Neubauer, Andreas and Sch{\"a}fer-Eckart, Kerstin and Schliemann, Christoph and Krause, Stefan W. and Herbst, Regina and H{\"a}nel, Mathias and Frickhofen, Norbert and Noppeney, Richard and Kaiser, Ulrich and Baldus, Claudia D. and Kaufmann, Martin and R{\´a}cil, Zdenek and Platzbecker, Uwe and Berdel, Wolfgang E. and Mayer, Jiř{\´i} and Serve, Hubert and M{\"u}ller-Tidow, Carsten and Ehninger, Gerhard and St{\"o}lzel, Friedrich and Kroschinsky, Frank and Schetelig, Johannes and Bornh{\"a}user, Martin and Thiede, Christian and Middeke, Jan Moritz}, title = {Loss-of-function mutations of BCOR are an independent marker of adverse outcomes in intensively treated patients with acute myeloid leukemia}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {9}, issn = {2072-6694}, doi = {10.3390/cancers13092095}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236735}, year = {2021}, abstract = {Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The BCL6 corepressor (BCOR) and its homolog, the BCL6 corepressor-like 1 (BCORL1), have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML. BCOR and BCORL1 mutations were found in 71 (4.6\%) and 53 patients (3.5\%), respectively. Frequently co-mutated genes were DNTM3A, TET2 and RUNX1. Mutated BCORL1 and loss-of-function mutations of BCOR were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of BCOR had a significantly reduced median event-free survival (HR = 1.464 (95\%-Confidence Interval (CI): 1.005-2.134), p = 0.047), relapse-free survival (HR = 1.904 (95\%-CI: 1.163-3.117), p = 0.01), and trend for reduced overall survival (HR = 1.495 (95\%-CI: 0.990-2.258), p = 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of BCOR regarding risk stratification in AML, which may influence treatment allocation.}, language = {en} }