TY - JOUR A1 - Maurus, K. A1 - Kosnopfel, C. A1 - Kneitz, H. A1 - Appenzeller, S. A1 - Schrama, D. A1 - Glutsch, V. A1 - Roth, S. A1 - Gerhard-Hartmann, E. A1 - Rosenfeldt, M. A1 - Möhrmann, L. A1 - Fröhlich, M. A1 - Hübschmann, D. A1 - Stenzinger, A. A1 - Glimm, H. A1 - Fröhling, S. A1 - Goebeler, M. A1 - Rosenwald, A. A1 - Kutzner, H. A1 - Schilling, B. T1 - Cutaneous epithelioid haemangiomas show somatic mutations in the mitogen-activated protein kinase pathway JF - British Journal of Dermatology N2 - Background Epithelioid haemangioma (EH) arising from the skin is a benign vascular tumour with marked inflammatory cell infiltration, which exhibits a high tendency to persist and frequently recurs after resection. So far, the underlying pathogenesis is largely elusive. Objectives To identify genetic alterations by next-generation sequencing and/or droplet digital polymerase chain reaction (ddPCR) in cutaneous EH. Methods DNA and RNA from an EH lesion of an index patient were subjected to whole-genome and RNA sequencing. Multiplex PCR-based panel sequencing of genomic DNA isolated from archival formalin-fixed paraffin-embedded tissue of 18 patients with cutaneous EH was performed. ddPCR was used to confirm mutations. Results We identified somatic mutations in genes of the mitogen-activated protein kinase (MAPK) pathway (MAP2K1 and KRAS) in cutaneous EH biopsies. By ddPCR we could confirm the recurrent presence of activating, low-frequency mutations affecting MAP2K1. In total, nine out of 18 patients analysed showed activating MAPK pathway mutations, which were mutually exclusive. Comparative analysis of tissue areas enriched for lymphatic infiltrate or aberrant endothelial cells, respectively, revealed an association of these mutations with the presence of endothelial cells. Conclusions Taken together, our data suggest that EH shows somatic mutations in genes of the MAPK pathway which might contribute to the formation of this benign tumour. KW - protein kinase pathway KW - Background Epithelioid haemangioma KW - somatic mutations Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258333 VL - 186 IS - 3 ER - TY - JOUR A1 - Mainz, Laura A1 - Sarhan, Mohamed A. F. E. A1 - Roth, Sabine A1 - Sauer, Ursula A1 - Maurus, Katja A1 - Hartmann, Elena M. A1 - Seibert, Helen-Desiree A1 - Rosenwald, Andreas A1 - Diefenbacher, Markus E. A1 - Rosenfeldt, Mathias T. T1 - Autophagy blockage reduces the incidence of pancreatic ductal adenocarcinoma in the context of mutant Trp53 JF - Frontiers in Cell and Developmental Biology N2 - 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. KW - pancreatic cancer KW - autophagy KW - p53 KW - metastasis KW - ATG7 Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266005 SN - 2296-634X VL - 10 ER - TY - JOUR A1 - Rosenfeldt, Mathias T. A1 - Hartmann, Elena M. A1 - Leng, Corinna A1 - Rosenwald, Andreas A1 - Anagnostopoulos, Ioannis T1 - A case of nodular lymphocyte predominant Hodgkin lymphoma with unexpected EBV-latency type JF - Annals of Hematology N2 - No abstract available. KW - nodular lymphcyte KW - Hodgkin lymphoma Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232571 SN - 0939-5555 VL - 100 ER - TY - JOUR A1 - Prieto‐Garcia, Cristian A1 - Hartmann, Oliver A1 - Reissland, Michaela A1 - Braun, Fabian A1 - Fischer, Thomas A1 - Walz, Susanne A1 - Schülein‐Völk, Christina A1 - Eilers, Ursula A1 - Ade, Carsten P. A1 - Calzado, Marco A. A1 - Orian, Amir A1 - Maric, Hans M. A1 - Münch, Christian A1 - Rosenfeldt, Mathias A1 - Eilers, Martin A1 - Diefenbacher, Markus E. T1 - Maintaining protein stability of ∆Np63 via USP28 is required by squamous cancer cells JF - EMBO Molecular Medicine N2 - The transcription factor ∆Np63 is a master regulator of epithelial cell identity and essential for the survival of squamous cell carcinoma (SCC) of lung, head and neck, oesophagus, cervix and skin. Here, we report that the deubiquitylase USP28 stabilizes ∆Np63 and maintains elevated ∆NP63 levels in SCC by counteracting its proteasome‐mediated degradation. Impaired USP28 activity, either genetically or pharmacologically, abrogates the transcriptional identity and suppresses growth and survival of human SCC cells. CRISPR/Cas9‐engineered in vivo mouse models establish that endogenous USP28 is strictly required for both induction and maintenance of lung SCC. Our data strongly suggest that targeting ∆Np63 abundance via inhibition of USP28 is a promising strategy for the treatment of SCC tumours. KW - ∆Np63 KW - NOTCH KW - squamous cell carcinoma KW - 28 Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218303 VL - 12 IS - 4 ER -