@article{PorubskyPopovicBadveetal.2021,
  author    = {Porubsky, Stefan and Popovic, Zoran V. and Badve, Sunil and Banz, Yara and Berezowska, Sabina and Borchert, Dietmar and Br{\"u}ggemann, Monika and Gaiser, Timo and Graeter, Thomas and Hollaus, Peter and Huettl, Katrin S. and Kotrova, Michaela and Kreft, Andreas and Kugler, Christian and L{\"o}tscher, Fabian and M{\"o}ller, Burkhard and Ott, German and Preissler, Gerhard and Roessner, Eric and Rosenwald, Andreas and Str{\"o}bel, Philipp and Marx, Alexander},
  title     = {Thymic hyperplasia with lymphoepithelial sialadenitis (LESA)-like features: strong association with lymphomas and non-myasthenic autoimmune diseases},
  series = {Cancers},
  volume    = {13},
  journal   = {Cancers},
  number    = {2},
  issn      = {2072-6694},
  doi       = {10.3390/cancers13020315},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223049},
  year      = {2021},
  abstract  = {Thymic hyperplasia (TH) with lymphoepithelial sialadenitis (LESA)-like features (LESA-like TH) has been described as a tumor-like, benign proliferation of thymic epithelial cells and lymphoid follicles. We aimed to determine the frequency of lymphoma and autoimmunity in LESA-like TH and performed retrospective analysis of cases with LESA-like TH and/or thymic MALT-lymphoma. Among 36 patients (21 males) with LESA-like TH (age 52 years, 32-80; lesion diameter 7.0 cm, 1-14.5; median, range), five (14\%) showed associated lymphomas, including four (11\%) thymic MALT lymphomas and one (3\%) diffuse large B-cell lymphoma. One additional case showed a clonal B-cell-receptor rearrangement without evidence of lymphoma. Twelve (33\%) patients (7 women) suffered from partially overlapping autoimmune diseases: systemic lupus erythematosus (n = 4, 11\%), rheumatoid arthritis (n = 3, 8\%), myasthenia gravis (n = 2, 6\%), asthma (n = 2, 6\%), scleroderma, Sj{\"o}gren syndrome, pure red cell aplasia, Grave's disease and anti-IgLON5 syndrome (each n = 1, 3\%). Among 11 primary thymic MALT lymphomas, remnants of LESA-like TH were found in two cases (18\%). In summary, LESA-like TH shows a striking association with autoimmunity and predisposes to lymphomas. Thus, a hematologic and rheumatologic workup should become standard in patients diagnosed with LESA-like TH. Radiologists and clinicians should be aware of LESA-like TH as a differential diagnosis for mediastinal mass lesions in patients with autoimmune diseases.},
  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{ShaikhVargasMokhtarietal.2021,
  author    = {Shaikh, Haroon and Vargas, Juan Gamboa and Mokhtari, Zeinab and Jarick, Katja J. and Ulbrich, Maria and Mosca, Josefina Pe{\~n}a and Viera, Estibaliz Arellano and Graf, Caroline and Le, Duc-Dung and Heinze, Katrin G. and B{\"u}ttner-Herold, Maike and Rosenwald, Andreas and Pezoldt, Joern and Huehn, Jochen and Beilhack, Andreas},
  title     = {Mesenteric Lymph Node Transplantation in Mice to Study Immune Responses of the Gastrointestinal Tract},
  series = {Frontiers in Immunology},
  volume    = {12},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2021.689896},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-244869},
  year      = {2021},
  abstract  = {Mesenteric lymph nodes (mLNs) are sentinel sites of enteral immunosurveillance and immune homeostasis. Immune cells from the gastrointestinal tract (GIT) are constantly recruited to the mLNs in steady-state and under inflammatory conditions resulting in the induction of tolerance and immune cells activation, respectively. Surgical dissection and transplantation of lymph nodes (LN) is a technique that has supported seminal work to study LN function and is useful to investigate resident stromal and endothelial cell biology and their cellular interactions in experimental disease models. Here, we provide a detailed protocol of syngeneic mLN transplantation and report assays to analyze effective mLN engraftment in congenic recipients. Transplanted mLNs allow to study T cell activation and proliferation in preclinical mouse models. Donor mLNs proved viable and functional after surgical transplantation and regenerated blood and lymphatic vessels. Immune cells from the host completely colonized the transplanted mLNs within 7-8 weeks after the surgical intervention. After allogeneic hematopoietic cell transplantation (allo-HCT), adoptively transferred allogeneic CD4+ T cells from FVB/N (H-2q) mice homed to the transplanted mLNs in C57BL/6 (H-2b) recipients during the initiation phase of acute graft-versus-host disease (aGvHD). These CD4+ T cells retained full proliferative capacity and upregulated effector and gut homing molecules comparable to those in mLNs from unmanipulated wild-type recipients. Wild type mLNs transplanted into MHCII deficient syngeneic hosts sufficed to activate alloreactive T cells upon allogeneic hematopoietic cell transplantation, even in the absence of MHCII+ CD11c+ myeloid cells. These data support that orthotopically transplanted mLNs maintain physiological functions after transplantation. The technique of LN transplantation can be applied to study migratory and resident cell compartment interactions in mLNs as well as immune reactions from and to the gut under inflammatory and non-inflammatory conditions.},
  language  = {en}
}
@article{MajumderJugovicSauletal.2021,
  author    = {Majumder, Snigdha and Jugovic, Isabelle and Saul, Domenica and Bell, Luisa and Hundhausen, Nadine and Seal, Rishav and Beilhack, Andreas and Rosenwald, Andreas and Mougiakakos, Dimitrios and Berberich-Siebelt, Friederike},
  title     = {Rapid and Efficient Gene Editing for Direct Transplantation of Naive Murine Cas9\(^+\) T Cells},
  series = {Frontiers in Immunology},
  volume    = {12},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2021.683631},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-242896},
  year      = {2021},
  abstract  = {Gene editing of primary T cells is a difficult task. However, it is important for research and especially for clinical T-cell transfers. CRISPR/Cas9 is the most powerful gene-editing technique. It has to be applied to cells by either retroviral transduction or electroporation of ribonucleoprotein complexes. Only the latter is possible with resting T cells. Here, we make use of Cas9 transgenic mice and demonstrate nucleofection of pre-stimulated and, importantly, of naive CD3\(^+\) T cells with guideRNA only. This proved to be rapid and efficient with no need of further selection. In the mixture of Cas9\(^+\)CD3\(^+\) T cells, CD4\(^+\) and CD8\(^+\) conventional as well as regulatory T cells were targeted concurrently. IL-7 supported survival and naivety in vitro, but T cells were also transplantable immediately after nucleofection and elicited their function like unprocessed T cells. Accordingly, metabolic reprogramming reached normal levels within days. In a major mismatch model of GvHD, not only ablation of NFATc1 and/or NFATc2, but also of the NFAT-target gene IRF4 in na{\"i}ve primary murine Cas9\(^+\)CD3\(^+\) T cells by gRNA-only nucleofection ameliorated GvHD. However, pre-activated murine T cells could not achieve long-term protection from GvHD upon single NFATc1 or NFATc2 knockout. This emphasizes the necessity of gene-editing and transferring unstimulated human T cells during allogenic hematopoietic stem cell transplantation.},
  language  = {en}
}
@article{GerhardHartmannWiegeringBenoitetal.2021,
  author    = {Gerhard-Hartmann, Elena and Wiegering, Verena and Benoit, Clemens and Meyer, Thomas and Rosenwald, Andreas and Maurus, Katja and Ernestus, Karen},
  title     = {A large retroperitoneal lipoblastoma as an incidental finding: a case report},
  series = {BMC Pediatrics},
  volume    = {21},
  journal   = {BMC Pediatrics},
  doi       = {10.1186/s12887-021-02628-w},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260173},
  year      = {2021},
  abstract  = {Background Lipoblastoma is a rare benign mesenchymal neoplasm of infancy that most commonly occurs on the extremities and trunk but can arise at variable sites of the body. Retroperitoneal lipoblastomas are particularly rare but can grow to enormous size, and preoperative diagnosis is difficult with diverse, mostly malignant differential diagnoses that would lead to aggressive therapy. Since lipoblastoma is a benign tumor that has an excellent prognosis after resection, correct diagnosis is crucial. Case presentation A case of a large retroperitoneal tumor of a 24-month old infant that was clinically suspicious of a malignant tumor is presented. Due to proximity to the right kidney, clinically most probably a nephroblastoma or clear cell sarcoma of the kidney was suspected. Radiological findings were ambiguous. Therefore, the mass was biopsied, and histology revealed an adipocytic lesion. Although mostly composed of mature adipocytes, in view of the age of the patient, the differential diagnosis of a (maturing) lipoblastoma was raised, which was supported by molecular analysis demonstrating a HAS2-PLAG1 fusion. The tumor was completely resected, and further histopathological workup led to the final diagnosis of a 13 cm large retroperitoneal maturing lipoblastoma. The child recovered promptly from surgery and showed no evidence of recurrence so far. Conclusion Although rare, lipoblastoma should be included in the differential diagnoses of retroperitoneal tumors in infants and children, and molecular diagnostic approaches could be a helpful diagnostic adjunct in challenging cases.},
  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}
}
@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{GaritanoTrojaolaSanchoGoetzetal.2021,
  author    = {Garitano-Trojaola, Andoni and Sancho, Ana and G{\"o}tz, Ralph and Eiring, Patrick and Walz, Susanne and Jetani, Hardikkumar and Gil-Pulido, Jesus and Da Via, Matteo Claudio and Teufel, Eva and Rhodes, Nadine and Haertle, Larissa and Arellano-Viera, Estibaliz and Tibes, Raoul and Rosenwald, Andreas and Rasche, Leo and Hudecek, Michael and Sauer, Markus and Groll, J{\"u}rgen and Einsele, Hermann and Kraus, Sabrina and Kort{\"u}m, Martin K.},
  title     = {Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia},
  series = {Communications Biology},
  volume    = {4},
  journal   = {Communications Biology},
  number    = {1},
  doi       = {10.1038/s42003-021-02215-w},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260709},
  year      = {2021},
  abstract  = {The presence of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with an unfavorable prognosis. FLT3 inhibitors, such as midostaurin, are used clinically but fail to entirely eradicate FLT3-ITD+AML. This study introduces a new perspective and highlights the impact of RAC1-dependent actin cytoskeleton remodeling on resistance to midostaurin in AML. RAC1 hyperactivation leads resistance via hyperphosphorylation of the positive regulator of actin polymerization N-WASP and antiapoptotic BCL-2. RAC1/N-WASP, through ARP2/3 complex activation, increases the number of actin filaments, cell stiffness and adhesion forces to mesenchymal stromal cells (MSCs) being identified as a biomarker of resistance. Midostaurin resistance can be overcome by a combination of midostaruin, the BCL-2 inhibitor venetoclax and the RAC1 inhibitor Eht1864 in midostaurin-resistant AML cell lines and primary samples, providing the first evidence of a potential new treatment approach to eradicate FLT3-ITD+AML. Garitano-Trojaola et al. used a combination of human acute myeloid leukemia (AML) cell lines and primary samples to show that RAC1-dependent actin cytoskeleton remodeling through BCL2 family plays a key role in resistance to the FLT3 inhibitor, Midostaurin in AML. They showed that by targeting RAC1 and BCL2, Midostaurin resistance was diminished, which potentially paves the way for an innovate treatment approach for FLT3 mutant AML.},
  language  = {en}
}
@article{RosenfeldtHartmannLengetal.2021,
  author    = {Rosenfeldt, Mathias T. and Hartmann, Elena M. and Leng, Corinna and Rosenwald, Andreas and Anagnostopoulos, Ioannis},
  title     = {A case of nodular lymphocyte predominant Hodgkin lymphoma with unexpected EBV-latency type},
  series = {Annals of Hematology},
  volume    = {100},
  journal   = {Annals of Hematology},
  issn      = {0939-5555},
  doi       = {10.1007/s00277-020-04174-4},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232571},
  pages     = {2635-2637},
  year      = {2021},
  abstract  = {No abstract available.},
  language  = {en}
}
@article{MarquardtSolimandoKerscheretal.2021,
  author    = {Marquardt, Andr{\´e} and Solimando, Antonio Giovanni and Kerscher, Alexander and Bittrich, Max and Kalogirou, Charis and K{\"u}bler, Hubert and Rosenwald, Andreas and Bargou, Ralf and Kollmannsberger, Philip and Schilling, Bastian and Meierjohann, Svenja and Krebs, Markus},
  title     = {Subgroup-Independent Mapping of Renal Cell Carcinoma — Machine Learning Reveals Prognostic Mitochondrial Gene Signature Beyond Histopathologic Boundaries},
  series = {Frontiers in Oncology},
  volume    = {11},
  journal   = {Frontiers in Oncology},
  issn      = {2234-943X},
  doi       = {10.3389/fonc.2021.621278},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232107},
  year      = {2021},
  abstract  = {Background: Renal cell carcinoma (RCC) is divided into three major histopathologic groups—clear cell (ccRCC), papillary (pRCC) and chromophobe RCC (chRCC). We performed a comprehensive re-analysis of publicly available RCC datasets from the TCGA (The Cancer Genome Atlas) database, thereby combining samples from all three subgroups, for an exploratory transcriptome profiling of RCC subgroups. Materials and Methods: We used FPKM (fragments per kilobase per million) files derived from the ccRCC, pRCC and chRCC cohorts of the TCGA database, representing transcriptomic data of 891 patients. Using principal component analysis, we visualized datasets as t-SNE plot for cluster detection. Clusters were characterized by machine learning, resulting gene signatures were validated by correlation analyses in the TCGA dataset and three external datasets (ICGC RECA-EU, CPTAC-3-Kidney, and GSE157256). Results: Many RCC samples co-clustered according to histopathology. However, a substantial number of samples clustered independently from histopathologic origin (mixed subgroup)—demonstrating divergence between histopathology and transcriptomic data. Further analyses of mixed subgroup via machine learning revealed a predominant mitochondrial gene signature—a trait previously known for chRCC—across all histopathologic subgroups. Additionally, ccRCC samples from mixed subgroup presented an inverse correlation of mitochondrial and angiogenesis-related genes in the TCGA and in three external validation cohorts. Moreover, mixed subgroup affiliation was associated with a highly significant shorter overall survival for patients with ccRCC—and a highly significant longer overall survival for chRCC patients. Conclusions: Pan-RCC clustering according to RNA-sequencing data revealed a distinct histology-independent subgroup characterized by strengthened mitochondrial and weakened angiogenesis-related gene signatures. Moreover, affiliation to mixed subgroup went along with a significantly shorter overall survival for ccRCC and a longer overall survival for chRCC patients. Further research could offer a therapy stratification by specifically addressing the mitochondrial metabolism of such tumors and its microenvironment.},
  language  = {en}
}