@article{MurtiFenderGlatzleetal.2023,
  author    = {Murti, Krisna and Fender, Hendrik and Glatzle, Carolin and Wismer, Rhoda and Sampere-Birlanga, Salvador and Wild, Vanessa and Muhammad, Khalid and Rosenwald, Andreas and Serfling, Edgar and Avots, Andris},
  title     = {Calcineurin-independent NFATc1 signaling is essential for survival of Burkitt lymphoma cells},
  series = {Frontiers in Oncology},
  volume    = {13},
  journal   = {Frontiers in Oncology},
  doi       = {10.3389/fonc.2023.1205788},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323103},
  year      = {2023},
  abstract  = {In Burkitt lymphoma (BL), a tumor of germinal center B cells, the pro-apoptotic properties of MYC are controlled by tonic B cell receptor (BCR) signals. Since BL cells do not exhibit constitutive NF-κB activity, we hypothesized that anti-apoptotic NFATc1 proteins provide a major transcriptional survival signal in BL. Here we show that post-transcriptional mechanisms are responsible for the calcineurin (CN) independent constitutive nuclear over-expression of NFATc1 in BL and Eµ-MYC - induced B cell lymphomas (BCL). Conditional inactivation of the Nfatc1 gene in B cells of Eµ-MYC mice leads to apoptosis of BCL cells in vivo and ex vivo. Inhibition of BCR/SYK/BTK/PI3K signals in BL cells results in cytosolic re-location of NFATc1 and apoptosis. Therefore, NFATc1 activity is an integrated part of tonic BCR signaling and an alternative target for therapeutic intervention in BL.},
  language  = {en}
}
@article{SealSchwabChiarollaetal.2023,
  author    = {Seal, Rishav and Schwab, Lara S. U. and Chiarolla, Cristina M. and Hundhausen, Nadine and Klose, Georg Heinrich and Reu-Hofer, Simone and Rosenwald, Andreas and Wiest, Johannes and Berberich-Siebelt, Friederike},
  title     = {Delayed and limited administration of the JAKinib tofacitinib mitigates chronic DSS-induced colitis},
  series = {Frontiers in Immunology},
  volume    = {14},
  journal   = {Frontiers in Immunology},
  doi       = {10.3389/fimmu.2023.1179311},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-317815},
  year      = {2023},
  abstract  = {In inflammatory bowel disease, dysregulated T cells express pro-inflammatory cytokines. Using a chronic azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis model resembling ulcerative colitis, we evaluated whether and when treatment with the Janus kinase (JAK) inhibitor tofacitinib could be curative. Comparing the treatment with two and three cycles of tofacitinib medication in drinking water - intermittently with DSS induction - revealed that two cycles were not only sufficient but also superior over the 3-x regimen. The two cycles of the 2-x protocol paralleled the second and third cycles of the longer protocol. T cells were less able to express interferon gamma (IFN-γ) and the serum levels of IFN-γ, interleukin (IL)-2, IL-6, IL-17, and tumor necrosis factor (TNF) were significantly reduced in sera, while those of IL-10 and IL-22 increased under the 2-x protocol. Likewise, the frequency and effector phenotype of regulatory T cells (Tregs) increased. This was accompanied by normal weight gain, controlled clinical scores, and restored stool consistency. The general and histologic appearance of the colons revealed healing and tissue intactness. Importantly, two phases of tofacitinib medication completely prevented AOM-incited pseudopolyps and the hyper-proliferation of epithelia, which was in contrast to the 3-x regimen. This implies that the initial IBD-induced cytokine expression is not necessarily harmful as long as inflammatory signaling can later be suppressed and that time-restricted treatment allows for anti-inflammatory and tissue-healing cytokine activities.},
  language  = {en}
}
@article{BoeckMaurusGerhardHartmannetal.2023,
  author    = {B{\"o}ck, Julia and Maurus, Katja and Gerhard-Hartmann, Elena and Br{\"a}ndlein, Stephanie and Kurz, Katrin S. and Ott, German and Anagnostopoulos, Ioannis and Rosenwald, Andreas and Zam{\`o}, Alberto},
  title     = {Targeted panel sequencing in the routine diagnosis of mature T- and NK-cell lymphomas},
  series = {Frontiers in Oncology},
  volume    = {13},
  journal   = {Frontiers in Oncology},
  issn      = {2234-943X},
  doi       = {10.3389/fonc.2023.1231601},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-326478},
  year      = {2023},
  abstract  = {Diagnosing any of the more than 30 types of T-cell lymphomas is considered a challenging task for many pathologists and currently requires morphological expertise as well as the integration of clinical data, immunophenotype, flow cytometry and clonality analyses. Even considering all available information, some margin of doubt might remain using the current diagnostic procedures. In recent times, the genetic landscape of most T-cell lymphomas has been elucidated, showing a number of diagnostically relevant mutations. In addition, recent data indicate that some of these genetic alterations might bear prognostic and predictive value. Extensive genetic analyses, such as whole exome or large panel sequencing are still expensive and time consuming, therefore limiting their application in routine diagnostic. We therefore devoted our effort to develop a lean approach for genetic analysis of T-cell lymphomas, focusing on maximum efficiency rather than exhaustively covering all possible targets. Here we report the results generated with our small amplicon-based panel that could be used routinely on paraffin-embedded and even decalcified samples, on a single sample basis in parallel with other NGS-panels used in our routine diagnostic lab, in a relatively short time and with limited costs. We tested 128 available samples from two German reference centers as part of our routine work up (among which 116 T-cell lymphomas), which is the largest routine diagnostic series reported to date. Our results showed that this assay had a very high rate of technical success (97\%) and could detect mutations in the majority (79\%) of tested T-cell lymphoma samples.},
  language  = {en}
}
@article{ZamoGerhardHartmannOttetal.2022,
  author    = {Zam{\`o}, Alberto and Gerhard-Hartmann, Elena and Ott, German and Anagnostopoulos, Ioannis and Scott, David W. and Rosenwald, Andreas and Rauert-Wunderlich, Hilka},
  title     = {Routine application of the Lymph2Cx assay for the subclassification of aggressive B-cell lymphoma: report of a prospective real-world series},
  series = {Virchows Archiv},
  volume    = {481},
  journal   = {Virchows Archiv},
  number    = {6},
  doi       = {10.1007/s00428-022-03420-6},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324686},
  pages     = {935-943},
  year      = {2022},
  abstract  = {The subclassification of diffuse large B-cell lymphoma (DLBCL) into germinal center B-cell-like (GCB) and activated B-cell-like (ABC) subtypes has become mandatory in the 2017 update of the WHO classification of lymphoid neoplasms and will continue to be used in the WHO 5\(^{th}\) edition. The RNA-based Lymph2Cx assay has been validated as a reliable surrogate of high-throughput gene expression profiling assays for distinguishing between GCB and ABC DLBCL and provides reliable results from formalin-fixed, paraffin-embedded (FFPE) material. This test has been previously used in clinical trials, but experience from real-world routine application is rare. We routinely applied the Lymph2Cx assay to day-to-day diagnostics on a series of 147 aggressive B-cell lymphoma cases and correlated our results with the immunohistochemical subclassification using the Hans algorithm and fluorescence in situ hybridization findings using break-apart probes for MYC, BCL2, and BCL6. The routine use of the Lymph2Cx assay had a high technical success rate (94.6\%) with a low rate of failure due to poor material and/or RNA quality. The Lymph2Cx assay was discordant with the Hans algorithm in 18\% (23 of 128 cases). Discordant cases were mainly classified as GCB by the Hans algorithm and as ABC by Lymph2Cx (n = 11, 8.6\%). Only 5 cases (3.9\%) were classified as non-GCB by the Hans algorithm and as GCB by Lymph2Cx. Additionally, 5.5\% of cases (n = 7) were left unclassified by Lymph2Cx, whereas they were defined as GCB (n = 4) or non-GCB (n = 3) by the Hans algorithm. Our data support the routine applicability of the Lymph2Cx assay.},
  language  = {en}
}
@article{HrudkaEisHeřmanetal.2019,
  author    = {Hrudka, Jan and Eis, V{\´a}clav and Heřman, Josef and Prouzov{\´a}, Zuzana and Rosenwald, Andreas and František, Duška},
  title     = {Panniculitis-like T-cell-lymphoma in the mesentery associated with hemophagocytic syndrome: autopsy case report},
  series = {Diagnostic Pathology},
  volume    = {14},
  journal   = {Diagnostic Pathology},
  doi       = {10.1186/s13000-019-0854-9},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-322665},
  year      = {2019},
  abstract  = {Background Panniculitis-like T-cell lymphoma is an uncommon type of non-Hodgkin lymphoma, occurring usually in the form of nodules within the subcutaneous fat tissue of the extremities or trunk. In the literature, subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is described as a distinct type of T-cell lymphoma with a variable clinical behavior, depending on molecular phenotype of T-cell receptor (TCR) and on the presence or absence of hemophagocytic syndrome. Case presentation We present a bioptic and autoptic case of a 65-years old Caucasian man with panniculitic T-cell lymphoma with morphological and immunohistochemical features of SPTCL, limited to the retroperitoneal and mesenteric mass, i.e. without any cutaneous involvement, and associated with severe hemophagocytic lymphohistiocytosis. Conclusion A panniculitic T-cell lymphoma with morphological and molecular features of SPTCL, which is limited to mesentery, i.e. does not involve subcutaneous fat, seems to be exceedingly rare.},
  language  = {en}
}
@article{NicklEckGoedertetal.2023,
  author    = {Nickl, Vera and Eck, Juliana and Goedert, Nicolas and H{\"u}bner, Julian and Nerreter, Thomas and Hagemann, Carsten and Ernestus, Ralf-Ingo and Schulz, Tim and Nickl, Robert Carl and Keßler, Almuth Friederike and L{\"o}hr, Mario and Rosenwald, Andreas and Breun, Maria and Monoranu, Camelia Maria},
  title     = {Characterization and optimization of the tumor microenvironment in patient-derived organotypic slices and organoid models of glioblastoma},
  series = {Cancers},
  volume    = {15},
  journal   = {Cancers},
  number    = {10},
  issn      = {2072-6694},
  doi       = {10.3390/cancers15102698},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319249},
  year      = {2023},
  abstract  = {While glioblastoma (GBM) is still challenging to treat, novel immunotherapeutic approaches have shown promising effects in preclinical settings. However, their clinical breakthrough is hampered by complex interactions of GBM with the tumor microenvironment (TME). Here, we present an analysis of TME composition in a patient-derived organoid model (PDO) as well as in organotypic slice cultures (OSC). To obtain a more realistic model for immunotherapeutic testing, we introduce an enhanced PDO model. We manufactured PDOs and OSCs from fresh tissue of GBM patients and analyzed the TME. Enhanced PDOs (ePDOs) were obtained via co-culture with PBMCs (peripheral blood mononuclear cells) and compared to normal PDOs (nPDOs) and PT (primary tissue). At first, we showed that TME was not sustained in PDOs after a short time of culture. In contrast, TME was largely maintained in OSCs. Unfortunately, OSCs can only be cultured for up to 9 days. Thus, we enhanced the TME in PDOs by co-culturing PDOs and PBMCs from healthy donors. These cellular TME patterns could be preserved until day 21. The ePDO approach could mirror the interaction of GBM, TME and immunotherapeutic agents and may consequently represent a realistic model for individual immunotherapeutic drug testing in the future.},
  language  = {en}
}
@article{WobserSchummerAppenzelleretal.2022,
  author    = {Wobser, Marion and Schummer, Patrick and Appenzeller, Silke and Kneitz, Hermann and Roth, Sabine and Goebeler, Matthias and Geissinger, Eva and Rosenwald, Andreas and Maurus, Katja},
  title     = {Panel sequencing of primary cutaneous B-cell lymphoma},
  series = {Cancers},
  volume    = {14},
  journal   = {Cancers},
  number    = {21},
  issn      = {2072-6694},
  doi       = {10.3390/cancers14215274},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-290330},
  year      = {2022},
  abstract  = {Background: Primary cutaneous follicular B-cell lymphoma (PCFBCL) represents an indolent subtype of Non-Hodgkin's lymphomas, being clinically characterized by slowly growing tumors of the skin and common cutaneous relapses, while only exhibiting a low propensity for systemic dissemination or fatal outcome. Up to now, only few studies have investigated underlying molecular alterations of PCFBCL with respect to somatic mutations. Objectives: Our aim was to gain deeper insight into the pathogenesis of PCFBCL and to delineate discriminatory molecular features of this lymphoma subtype. Methods: We performed hybridization-based panel sequencing of 40 lymphoma-associated genes of 10 cases of well-characterized PCFBCL. In addition, we included two further ambiguous cases of atypical B-cell-rich lymphoid infiltrate/B-cell lymphoma of the skin for which definite subtype attribution had not been possible by routine investigations. Results: In 10 out of 12 analyzed cases, we identified genetic alterations within 15 of the selected 40 target genes. The most frequently detected alterations in PCFBCL affected the TNFRSF14, CREBBP, STAT6 and TP53 genes. Our analysis unrevealed novel mutations of the BCL2 gene in PCFBCL. All patients exhibited an indolent clinical course. Both the included arbitrary cases of atypical B-cell-rich cutaneous infiltrates showed somatic mutations within the FAS gene. As these mutations have previously been designated as subtype-specific recurrent alterations in primary cutaneous marginal zone lymphoma (PCMZL), we finally favored the diagnosis of PCMZL in these two cases based on these molecular findings. Conclusions: To conclude, our molecular data support that PCFBCL shows distinct somatic mutations which may aid to differentiate PCFBCL from pseudo-lymphoma as well as from other indolent and aggressive cutaneous B-cell lymphomas. While the detected genetic alterations of PCFBCL did not turn out to harbor any prognostic value in our cohort, our molecular data may add adjunctive discriminatory features for diagnostic purposes on a molecular level.},
  language  = {en}
}
@article{LuekeHallerUtpateletal.2022,
  author    = {L{\"u}ke, Florian and Haller, Florian and Utpatel, Kirsten and Krebs, Markus and Meidenbauer, Norbert and Scheiter, Alexander and Spoerl, Silvia and Heudobler, Daniel and Sparrer, Daniela and Kaiser, Ulrich and Keil, Felix and Schubart, Christoph and T{\"o}gel, Lars and Einhell, Sabine and Dietmaier, Wolfgang and Huss, Ralf and Dintner, Sebastian and Sommer, Sebastian and Jordan, Frank and Goebeler, Maria-Elisabeth and Metz, Michaela and Haake, Diana and Scheytt, Mithun and Gerhard-Hartmann, Elena and Maurus, Katja and Br{\"a}ndlein, Stephanie and Rosenwald, Andreas and Hartmann, Arndt and M{\"a}rkl, Bruno and Einsele, Hermann and Mackensen, Andreas and Herr, Wolfgang and Kunzmann, Volker and Bargou, Ralf and Beckmann, Matthias W. and Pukrop, Tobias and Trepel, Martin and Evert, Matthias and Claus, Rainer and Kerscher, Alexander},
  title     = {Identification of disparities in personalized cancer care — a joint approach of the German WERA consortium},
  series = {Cancers},
  volume    = {14},
  journal   = {Cancers},
  number    = {20},
  issn      = {2072-6694},
  doi       = {10.3390/cancers14205040},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-290311},
  year      = {2022},
  abstract  = {(1) Background: molecular tumor boards (MTBs) are crucial instruments for discussing and allocating targeted therapies to suitable cancer patients based on genetic findings. Currently, limited evidence is available regarding the regional impact and the outreach component of MTBs; (2) Methods: we analyzed MTB patient data from four neighboring Bavarian tertiary care oncology centers in W{\"u}rzburg, Erlangen, Regensburg, and Augsburg, together constituting the WERA Alliance. Absolute patient numbers and regional distribution across the WERA-wide catchment area were weighted with local population densities; (3) Results: the highest MTB patient numbers were found close to the four cancer centers. However, peaks in absolute patient numbers were also detected in more distant and rural areas. Moreover, weighting absolute numbers with local population density allowed for identifying so-called white spots—regions within our catchment that were relatively underrepresented in WERA MTBs; (4) Conclusions: investigating patient data from four neighboring cancer centers, we comprehensively assessed the regional impact of our MTBs. The results confirmed the success of existing collaborative structures with our regional partners. Additionally, our results help identifying potential white spots in providing precision oncology and help establishing a joint WERA-wide outreach strategy.},
  language  = {en}
}
@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{WobserRothAppenzelleretal.2021,
  author    = {Wobser, Marion and Roth, Sabine and Appenzeller, Silke and Houben, Roland and Schrama, David and Goebeler, Matthias and Geissinger, Eva and Rosenwald, Andreas and Maurus, Katja},
  title     = {Targeted deep sequencing of mycosis fungoides reveals intracellular signaling pathways associated with aggressiveness and large cell transformation},
  series = {Cancers},
  volume    = {13},
  journal   = {Cancers},
  number    = {21},
  issn      = {2072-6694},
  doi       = {10.3390/cancers13215512},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250094},
  year      = {2021},
  abstract  = {Introduction: Large-cell transformation (LCT) of mycosis fungoides (MF) has been associated with a higher risk of relapse and progression and, consequently, restricted prognosis. Its molecular pathogenesis has not been elucidated yet. Materials and Methods: In order to address molecular mechanisms of LCT, we performed hybrid capture panel-based sequencing of skin biopsies from 10 patients suffering from MF with LCT versus 17 patients without LCT including follow-up biopsies during clinical course, respectively (51 samples in total). The analyzed patients were attributed to three different groups based on the presence of LCT and clinical behavior. Results: While indolent MF cases without LCT did not show pathogenic driver mutations, a high rate of oncogenic alterations was detected in patients with LCT and aggressive clinical courses. Various genes of different oncogenic signaling pathways, including the MAPK and JAK-STAT signaling pathways, as well as epigenetic modifiers were affected. A high inter-individual and distinctive intra-individual mutation diversity was observed. Oncogenic RAS mutations were exclusively detected in patients with LCT. Conclusion: Our data demonstrate that LCT transition of MF is associated with increased frequency of somatic mutations in cancer-associated genes. In particular, the activation of RAS signaling — together with epigenetic dysregulation — may crucially contribute to the molecular pathogenesis of the LCT phenotype, thus conveying its adverse clinical behavior.},
  language  = {en}
}
@article{FuhrHeidenreichSrivastavaetal.2022,
  author    = {Fuhr, Viktoria and Heidenreich, Shanice and Srivastava, Mugdha and Riedel, Angela and D{\"u}ll, Johannes and Gerhard-Hartmann, Elena and Rosenwald, Andreas and Rauert-Wunderlich, Hilka},
  title     = {CD52 and OXPHOS-potential targets in ibrutinib-treated mantle cell lymphoma},
  series = {Cell Death Discovery},
  volume    = {8},
  journal   = {Cell Death Discovery},
  issn      = {2058-7716},
  doi       = {10.1038/s41420-022-01289-7},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300817},
  year      = {2022},
  abstract  = {Altered features of tumor cells acquired across therapy can result in the survival of treatment-resistant clones that may cause minimal residual disease (MRD). Despite the efficacy of ibrutinib in treating relapsed/refractory mantle cell lymphoma, the obstacle of residual cells contributes to relapses of this mature B-cell neoplasm, and the disease remains incurable. RNA-seq analysis of an ibrutinib-sensitive mantle cell lymphoma cell line following ibrutinib incubation of up to 4 d, corroborated our previously postulated resistance mechanism of a metabolic switch to reliance on oxidative phosphorylation (OXPHOS) in surviving cells. Besides, we had shown that treatment-persisting cells were characterized by increased CD52 expression. Therefore, we hypothesized that combining ibrutinib with another agent targeting these potential escape mechanisms could minimize the risk of survival of ibrutinib-resistant cells. Concomitant use of ibrutinib with OXPHOS-inhibitor IACS-010759 increased toxicity compared to ibrutinib alone. Targeting CD52 was even more efficient, as addition of CD52 mAb in combination with human serum following ibrutinib pretreatment led to rapid complement-dependent-cytotoxicity in an ibrutinib-sensitive cell line. In primary mantle cell lymphoma cells, a higher toxic effect with CD52 mAb was obtained, when cells were pretreated with ibrutinib, but only in an ibrutinib-sensitive cohort. Given the challenge of treating multi-resistant mantle cell lymphoma patients, this work highlights the potential use of anti-CD52 therapy as consolidation after ibrutinib treatment in patients who responded to the BTK inhibitor to achieve MRD negativity and prolong progression-free survival.},
  language  = {en}
}
@article{LoefflerWirthKreuzHoppetal.2019,
  author    = {Loeffler-Wirth, Henry and Kreuz, Markus and Hopp, Lydia and Arakelyan, Arsen and Haake, Andrea and Cogliatti, Sergio B. and Feller, Alfred C. and Hansmann, Martin-Leo and Lenze, Dido and M{\"o}ller, Peter and M{\"u}ller-Hermelink, Hans Konrad and Fortenbacher, Erik and Willscher, Edith and Ott, German and Rosenwald, Andreas and Pott, Christiane and Schwaenen, Carsten and Trautmann, Heiko and Wessendorf, Swen and Stein, Harald and Szczepanowski, Monika and Tr{\"u}mper, Lorenz and Hummel, Michael and Klapper, Wolfram and Siebert, Reiner and Loeffler, Markus and Binder, Hans},
  title     = {A modular transcriptome map of mature B cell lymphomas},
  series = {Genome Medicine},
  volume    = {11},
  journal   = {Genome Medicine},
  doi       = {10.1186/s13073-019-0637-7},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237262},
  year      = {2019},
  abstract  = {Background Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma. Methods We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics. Results We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt's lymphoma and particularly on 'double-hit' MYC and BCL2 transformed lymphomas. Conclusions The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities.},
  language  = {en}
}
@article{OttoKastnerSchmidtetal.2022,
  author    = {Otto, Christoph and Kastner, Carolin and Schmidt, Stefanie and Uttinger, Konstantin and Baluapuri, Apoorva and Denk, Sarah and Rosenfeldt, Mathias T. and Rosenwald, Andreas and Roehrig, Florian and Ade, Carsten P. and Schuelein-Voelk, Christina and Diefenbacher, Markus E. and Germer, Christoph-Thomas and Wolf, Elmar and Eilers, Martin and Wiegering, Armin},
  title     = {RNA polymerase I inhibition induces terminal differentiation, growth arrest, and vulnerability to senolytics in colorectal cancer cells},
  series = {Molecular Oncology},
  volume    = {16},
  journal   = {Molecular Oncology},
  number    = {15},
  doi       = {10.1002/1878-0261.13265},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312806},
  pages     = {2788-2809},
  year      = {2022},
  abstract  = {Ribosomal biogenesis and protein synthesis are deregulated in most cancers, suggesting that interfering with translation machinery may hold significant therapeutic potential. Here, we show that loss of the tumor suppressor adenomatous polyposis coli (APC), which constitutes the initiating event in the adenoma carcinoma sequence for colorectal cancer (CRC), induces the expression of RNA polymerase I (RNAPOL1) transcription machinery, and subsequently upregulates ribosomal DNA (rDNA) transcription. Targeting RNAPOL1 with a specific inhibitor, CX5461, disrupts nucleolar integrity, and induces a disbalance of ribosomal proteins. Surprisingly, CX5461-induced growth arrest is irreversible and exhibits features of senescence and terminal differentiation. Mechanistically, CX5461 promotes differentiation in an MYC-interacting zinc-finger protein 1 (MIZ1)- and retinoblastoma protein (Rb)-dependent manner. In addition, the inhibition of RNAPOL1 renders CRC cells vulnerable towards senolytic agents. We validated this therapeutic effect of CX5461 in murine- and patient-derived organoids, and in a xenograft mouse model. These results show that targeting ribosomal biogenesis together with targeting the consecutive, senescent phenotype using approved drugs is a new therapeutic approach, which can rapidly be transferred from bench to bedside.},
  language  = {en}
}
@article{RitterZimmermannJoehrensetal.2018,
  author    = {Ritter, Julia and Zimmermann, Karin and J{\"o}hrens, Korinna and Mende, Stefanie and Seegebarth, Anke and Siegmund, Britta and Hennig, Steffen and Todorova, Kremena and Rosenwald, Andreas and Daum, Severin and Hummel, Michael and Schumann, Michael},
  title     = {T-cell repertoires in refractory coeliac disease},
  series = {Gut},
  volume    = {67},
  journal   = {Gut},
  number    = {4},
  doi       = {10.1136/gutjnl-2016-311816},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226350},
  pages     = {644-653},
  year      = {2018},
  abstract  = {Objective Refractory coeliac disease (RCD) is a potentially hazardous complication of coeliac disease (CD). In contrast to RCD type I, RCD type II is a precursor entity of enteropathy-associated T-cell lymphoma (EATL), which is associated with clonally expanding T-cells that are also found in the sequentially developing EATL. Using high-throughput sequencing (HTS), we aimed to establish the small-intestinal T-cell repertoire (TCR) in CD and RCD to unravel the role of distinct T-cell clonotypes in RCD pathogenesis. Design DNA extracted from duodenal mucosa specimens of controls (n=9), active coeliacs (n=10), coeliacs on a gluten-free diet (n=9), RCD type I (n= 8), RCD type II (n= 8) and unclassified Marsh I cases (n= 3) collected from 2002 to 2013 was examined by TCR beta-complementarity- determining regions 3 (CDR3) multiplex PCR followed by HTS of the amplicons. Results On average, 106 sequence reads per sample were generated consisting of up to 900 individual TCR beta rearrangements. In RCD type II, the most frequent clonotypes (ie, sequence reads with identical CDR3) represent in average 42.6\% of all TCR beta rearrangements, which was significantly higher than in controls (6.8\%; p<0.01) or RCD type I (6.7\%; p<0.01). Repeat endoscopies in individual patients revealed stability of clonotypes for up to several years without clinical symptoms of EATL. Dominant clonotypes identified in individual patients with RCD type II were unique and not related between patients. CD-associated, gliad-independent CDR3 motifs were only detectable at low frequencies. Conclusions TCR beta-HTS analysis unravels the TCR in CD and allows detailed analysis of individual TCR beta rearrangements. Dominant TCR beta sequences identified in patients with RCD type II are unique and not homologous to known gliadin-specific TCR sequences, supporting the assumption that these clonal T-cells expand independent of gluten stimulation.},
  language  = {en}
}
@article{PeindlGoettlichCrouchetal.2022,
  author    = {Peindl, Matthias and G{\"o}ttlich, Claudia and Crouch, Samantha and Hoff, Niklas and L{\"u}ttgens, Tamara and Schmitt, Franziska and Pereira, Jes{\´u}s Guillermo Nieves and May, Celina and Schliermann, Anna and Kronenthaler, Corinna and Cheufou, Danjouma and Reu-Hofer, Simone and Rosenwald, Andreas and Weigl, Elena and Walles, Thorsten and Sch{\"u}ler, Julia and Dandekar, Thomas and Nietzer, Sarah and Dandekar, Gudrun},
  title     = {EMT, stemness, and drug resistance in biological context: a 3D tumor tissue/in silico platform for analysis of combinatorial treatment in NSCLC with aggressive KRAS-biomarker signatures},
  series = {Cancers},
  volume    = {14},
  journal   = {Cancers},
  number    = {9},
  issn      = {2072-6694},
  doi       = {10.3390/cancers14092176},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270744},
  year      = {2022},
  abstract  = {Epithelial-to-mesenchymal transition (EMT) is discussed to be centrally involved in invasion, stemness, and drug resistance. Experimental models to evaluate this process in its biological complexity are limited. To shed light on EMT impact and test drug response more reliably, we use a lung tumor test system based on a decellularized intestinal matrix showing more in vivo-like proliferation levels and enhanced expression of clinical markers and carcinogenesis-related genes. In our models, we found evidence for a correlation of EMT with drug resistance in primary and secondary resistant cells harboring KRAS\(^{G12C}\) or EGFR mutations, which was simulated in silico based on an optimized signaling network topology. Notably, drug resistance did not correlate with EMT status in KRAS-mutated patient-derived xenograft (PDX) cell lines, and drug efficacy was not affected by EMT induction via TGF-β. To investigate further determinants of drug response, we tested several drugs in combination with a KRAS\(^{G12C}\) inhibitor in KRAS\(^{G12C}\) mutant HCC44 models, which, besides EMT, display mutations in P53, LKB1, KEAP1, and high c-MYC expression. We identified an aurora-kinase A (AURKA) inhibitor as the most promising candidate. In our network, AURKA is a centrally linked hub to EMT, proliferation, apoptosis, LKB1, and c-MYC. This exemplifies our systemic analysis approach for clinical translation of biomarker signatures.},
  language  = {en}
}
@article{Gerhard‐HartmannJoehrensSchinagletal.2022,
  author    = {Gerhard-Hartmann, Elena and J{\"o}hrens, Korinna and Schinagl, Lisa-Marie and Zam{\´o}, Alberto and Rosenwald, Andreas and Anagnostopoulos, Ioannis and Rosenfeldt, Mathias},
  title     = {Epstein-Barr virus infection patterns in nodular lymphocyte-predominant Hodgkin lymphoma},
  series = {Histopathology},
  volume    = {80},
  journal   = {Histopathology},
  number    = {7},
  doi       = {10.1111/his.14652},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-276327},
  pages     = {1071 -- 1080},
  year      = {2022},
  abstract  = {Aims To investigate Epstein-Barr virus (EBV) latency types in 19 cases of EBV-positive nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), as such information is currently incomplete. Methods and results Immunohistochemistry (IHC) for CD20, CD79a, PAX5, OCT2, CD30, CD15, CD3 and programmed cell death protein 1 was performed. For EBV detection, in-situ hybridisation (ISH) for EBV-encoded RNA (EBER) was employed combined with IHC for EBV-encoded latent membrane protein (LMP)-1, EBV-encoded nuclear antigen (EBNA)-2, and EBV-encoded BZLF1. In 95\% of the cases, neoplastic cells with features of Hodgkin and Reed-Sternberg (HRS) cells were present, mostly showing expression of CD30. In all cases, the B-cell phenotype was largely intact, and delineation from classic Hodgkin lymphoma (CHL) was further supported by myocyte enhancer factor 2B (MEF2B) detection. All tumour cells were EBER-positive except in two cases. EBV latency type II was most frequent (89\%) and type I was rare. Cases with latency type I were CD30-negative. Five cases contained some BZLF1-positive and/or EBNA-2-positive bystander lymphocytes. Conclusions As HRS morphology of neoplastic cells and CD30 expression are frequent features of EBV-positive NLPHL, preservation of the B-cell transcription programme, MEF2B expression combined with NLPHL-typical architecture and background composition facilitate distinction from CHL. EBER ISH is the method of choice to identify these cases. The majority present with EBV latency type II, and only rare cases present with latency type I, which can be associated with missing CD30 expression. The presence of occasional bystander lymphocytes expressing BZLF1 and/or EBNA-2 and the partial EBV infection of neoplastic cells in some cases could indicate that EBV is either not primarily involved or is only a transient driver in the pathogenesis of EBV-positive NLPHL.},
  language  = {en}
}
@article{MainzSarhanRothetal.2022,
  author    = {Mainz, Laura and Sarhan, Mohamed A. F. E. and Roth, Sabine and Sauer, Ursula and Maurus, Katja and Hartmann, Elena M. and Seibert, Helen-Desiree and Rosenwald, Andreas and Diefenbacher, Markus E. and Rosenfeldt, Mathias T.},
  title     = {Autophagy blockage reduces the incidence of pancreatic ductal adenocarcinoma in the context of mutant Trp53},
  series = {Frontiers in Cell and Developmental Biology},
  volume    = {10},
  journal   = {Frontiers in Cell and Developmental Biology},
  issn      = {2296-634X},
  doi       = {10.3389/fcell.2022.785252},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266005},
  year      = {2022},
  abstract  = {Macroautophagy (hereafter referred to as autophagy) is a homeostatic process that preserves cellular integrity. In mice, autophagy regulates pancreatic ductal adenocarcinoma (PDAC) development in a manner dependent on the status of the tumor suppressor gene Trp53. Studies published so far have investigated the impact of autophagy blockage in tumors arising from Trp53-hemizygous or -homozygous tissue. In contrast, in human PDACs the tumor suppressor gene TP53 is mutated rather than allelically lost, and TP53 mutants retain pathobiological functions that differ from complete allelic loss. In order to better represent the patient situation, we have investigated PDAC development in a well-characterized genetically engineered mouse model (GEMM) of PDAC with mutant Trp53 (Trp53\(^{R172H}\)) and deletion of the essential autophagy gene Atg7. Autophagy blockage reduced PDAC incidence but had no impact on survival time in the subset of animals that formed a tumor. In the absence of Atg7, non-tumor-bearing mice reached a similar age as animals with malignant disease. However, the architecture of autophagy-deficient, tumor-free pancreata was effaced, normal acinar tissue was largely replaced with low-grade pancreatic intraepithelial neoplasias (PanINs) and insulin expressing islet β-cells were reduced. Our data add further complexity to the interplay between Atg7 inhibition and Trp53 status in tumorigenesis.},
  language  = {en}
}
@article{RichterHuettmannRekowskietal.2019,
  author    = {Richter, Julia and H{\"u}ttmann, Andreas and Rekowski, Jan and Schmitz, Christine and G{\"a}rtner, Selina and Rosenwald, Andreas and Hansmann, Martin-Leo and Hartmann, Sylvia and M{\"o}ller, Peter and Wacker, Hans-Heinrich and Feller, Alfred and Thorns, Christoph and M{\"u}ller, Stefan and D{\"u}hrsen, Ulrich and Klapper, Wolfram},
  title     = {Molecular characteristics of diffuse large B-cell lymphoma in the Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin lymphomas (PETAL) trial: correlation with interim PET and outcome},
  series = {Blood Cancer Journal},
  volume    = {9},
  journal   = {Blood Cancer Journal},
  doi       = {10.1038/s41408-019-0230-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226185},
  pages     = {67},
  year      = {2019},
  abstract  = {No abstract available},
  language  = {en}
}
@article{SteinhardtKrummenastRosenwaldetal.2022,
  author    = {Steinhardt, Maximilian J. and Krummenast, Franziska C. and Rosenwald, Andreas and Gerhard-Hartmann, Elena and Heidemeier, Anke and Einsele, Hermann and Topp, Max S. and Duell, Johannes},
  title     = {R-CHOP intensification with mid-cycle methotrexate and consolidating AraC/TT with BCNU/aHSCT in primary aggressive lymphoma with CNS involvement},
  series = {Journal of Cancer Research and Clinical Oncology},
  volume    = {148},
  journal   = {Journal of Cancer Research and Clinical Oncology},
  number    = {1},
  issn      = {1432-1335},
  doi       = {10.1007/s00432-021-03663-x},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-267731},
  pages     = {205-214},
  year      = {2022},
  abstract  = {Purpose Patients suffering from aggressive systemic peripheral lymphoma with primary central nervous system involvement (PCL) are a rare and sparsely investigated population. Recommended treatment regimens include a combination of intrathecal and systemic chemotherapy as well as whole brain radiotherapy while offering relatively poor survival. Methods We conducted a single-center retrospective study that analyzed safety and outcome of 4 + 4 cycles Rituximab (R)-CHOP and R-high-dose Methotrexate (HD-MTX) for newly diagnosed, transplant-eligible patients ("Ping-Pong"), followed by Cytarabine (AraC)/Thiotepa (TT), BCNU/TT, and autologous hematologic stem cell transplantation (aHSCT). We retrospectively analyzed a set of 16 patients with high-intermediate or high-risk IPI status. Results Overall response rate to Ping-Pong was 100\% measured by CT/MRI, including 93.75\% complete remissions after BCNU/TT followed by PBSCT. One patient failed to qualify for high-dose chemotherapy due to progression when receiving Cytarabine/TT. All patients experienced grade III adverse events, 3 of them a grade IV adverse event. Estimated progression-free survival is 93.75\% after a 4.8-year follow-up currently. Conclusion Our study suggests high effectivity of R-CHOP with mid-cycle MTX with aHSCT consolidation towards acceptable OS results in this challenging patient population.},
  language  = {en}
}
@article{DanhofRascheMottoketal.2021,
  author    = {Danhof, Sophia and Rasche, Leo and Mottok, Anja and Steinm{\"u}ller, Tabea and Zhou, Xiang and Schreder, Martin and Kilian, Teresa and Strifler, Susanne and Rosenwald, Andreas and Hudecek, Michael and Einsele, Hermann and Gerhard-Hartmann, Elena},
  title     = {Elotuzumab for the treatment of extramedullary myeloma: a retrospective analysis of clinical efficacy and SLAMF7 expression patterns},
  series = {Annals of Hematology},
  volume    = {100},
  journal   = {Annals of Hematology},
  number    = {6},
  issn      = {1432-0584},
  doi       = {10.1007/s00277-021-04447-6},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266468},
  pages     = {1537-1546},
  year      = {2021},
  abstract  = {Extramedullary disease (EMD) represents a high-risk state of multiple myeloma (MM) associated with poor prognosis. While most anti-myeloma therapeutics demonstrate limited efficacy in this setting, some studies exploring the utility of chimeric antigen receptor (CAR)-modified T cells reported promising results. We have recently designed SLAMF7-directed CAR T cells for the treatment of MM. SLAMF7 is a transmembrane receptor expressed on myeloma cells that plays a role in myeloma cell homing to the bone marrow. Currently, the only approved anti-SLAMF7 therapeutic is the monoclonal antibody elotuzumab, but its efficacy in EMD has not been investigated thoroughly. Thus, we retrospectively analyzed the efficacy of elotuzumab-based combination therapy in a cohort of 15 patients with EMD. Moreover, since the presence of the target antigen is an indispensable prerequisite for effective targeted therapy, we investigated the SLAMF7 expression on extramedullary located tumor cells before and after treatment. We observed limited efficacy of elotuzumab-based combination therapies, with an overall response rate of 40\% and a progression-free and overall survival of 3.8 and 12.9 months, respectively. Before treatment initiation, all available EMD tissue specimens (n = 3) demonstrated a strong and consistent SLAMF7 surface expression by immunohistochemistry. Furthermore, to investigate a potential antigen reduction under therapeutic selection pressure, we analyzed samples of de novo EMD (n = 3) outgrown during elotuzumab treatment. Again, immunohistochemistry documented strong and consistent SLAMF7 expression in all samples. In aggregate, our data point towards a retained expression of SLAMF7 in EMD and encourage the development of more potent SLAMF7-directed immunotherapies, such as CAR T cells.},
  language  = {en}
}