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An Autochthonous Mouse Model of Myd88- and BCL2-Driven Diffuse Large B-cell Lymphoma Reveals Actionable Molecular Vulnerabilities.
Flümann, Ruth; Rehkämper, Tim; Nieper, Pascal; Pfeiffer, Pauline; Holzem, Alessandra; Klein, Sebastian; Bhatia, Sanil; Kochanek, Moritz; Kisis, Ilmars; Pelzer, Benedikt W; Ahlert, Heinz; Hauer, Julia; da Palma Guerreiro, Alexandra; Ryan, Jeremy A; Reimann, Maurice; Riabinska, Arina; Wiederstein, Janica; Krüger, Marcus; Deckert, Martina; Altmüller, Janine; Klatt, Andreas R; Frenzel, Lukas P; Pasqualucci, Laura; Béguelin, Wendy; Melnick, Ari M; Sander, Sandrine; Montesinos-Rongen, Manuel; Brunn, Anna; Lohneis, Philipp; Büttner, Reinhard; Kashkar, Hamid; Borkhardt, Arndt; Letai, Anthony; Persigehl, Thorsten; Peifer, Martin; Schmitt, Clemens A; Reinhardt, Hans Christian; Knittel, Gero.
Affiliation
  • Flümann R; University of Cologne, Faculty of Medicine and University Hospital Cologne, Clinic I of Internal Medicine, Cologne, Germany.
  • Rehkämper T; Center for Integrated Oncology, University of Cologne, Cologne, Germany.
  • Nieper P; Center for Molecular Medicine, University of Cologne, Cologne, Germany.
  • Pfeiffer P; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • Holzem A; University of Cologne, Faculty of Medicine and University Hospital Cologne, Clinic I of Internal Medicine, Cologne, Germany.
  • Klein S; Center for Integrated Oncology, University of Cologne, Cologne, Germany.
  • Bhatia S; Center for Molecular Medicine, University of Cologne, Cologne, Germany.
  • Kochanek M; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • Kisis I; University of Cologne, Faculty of Medicine and University Hospital Cologne, Clinic I of Internal Medicine, Cologne, Germany.
  • Pelzer BW; Center for Integrated Oncology, University of Cologne, Cologne, Germany.
  • Ahlert H; Center for Molecular Medicine, University of Cologne, Cologne, Germany.
  • Hauer J; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • da Palma Guerreiro A; University of Cologne, Faculty of Medicine and University Hospital Cologne, Clinic I of Internal Medicine, Cologne, Germany.
  • Ryan JA; Center for Integrated Oncology, University of Cologne, Cologne, Germany.
  • Reimann M; Center for Molecular Medicine, University of Cologne, Cologne, Germany.
  • Riabinska A; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • Wiederstein J; University of Cologne, Faculty of Medicine and University Hospital Cologne, Clinic I of Internal Medicine, Cologne, Germany.
  • Krüger M; Center for Integrated Oncology, University of Cologne, Cologne, Germany.
  • Deckert M; Center for Molecular Medicine, University of Cologne, Cologne, Germany.
  • Altmüller J; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • Klatt AR; Faculty of Medicine and University Hospital Cologne, Institute of Pathology, University of Cologne, Cologne, Germany.
  • Frenzel LP; Medical Faculty, Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • Pasqualucci L; University of Cologne, Faculty of Medicine and University Hospital Cologne, Clinic I of Internal Medicine, Cologne, Germany.
  • Béguelin W; Center for Integrated Oncology, University of Cologne, Cologne, Germany.
  • Melnick AM; Center for Molecular Medicine, University of Cologne, Cologne, Germany.
  • Sander S; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • Montesinos-Rongen M; University of Cologne, Faculty of Medicine and University Hospital Cologne, Clinic I of Internal Medicine, Cologne, Germany.
  • Brunn A; Center for Integrated Oncology, University of Cologne, Cologne, Germany.
  • Lohneis P; Center for Molecular Medicine, University of Cologne, Cologne, Germany.
  • Büttner R; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • Kashkar H; University of Cologne, Faculty of Medicine and University Hospital Cologne, Clinic I of Internal Medicine, Cologne, Germany.
  • Borkhardt A; Center for Integrated Oncology, University of Cologne, Cologne, Germany.
  • Letai A; Center for Molecular Medicine, University of Cologne, Cologne, Germany.
  • Persigehl T; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • Peifer M; Medical Faculty, Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • Schmitt CA; Department of Pediatrics, Pediatric Hematology and Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
  • Reinhardt HC; National Center for Tumor Diseases (NCT), Dresden, Germany.
  • Knittel G; University of Cologne, Faculty of Medicine and University Hospital Cologne, Clinic I of Internal Medicine, Cologne, Germany.
Blood Cancer Discov ; 2(1): 70-91, 2021 01.
Article in En | MEDLINE | ID: mdl-33447829
Based on gene expression profiles, diffuse large B cell lymphoma (DLBCL) is sub-divided into germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL. Two of the most common genomic aberrations in ABC-DLBCL are mutations in MYD88, as well as BCL2 copy number gains. Here, we employ immune phenotyping, RNA-Seq and whole exome sequencing to characterize a Myd88 and Bcl2-driven mouse model of ABC-DLBCL. We show that this model resembles features of human ABC-DLBCL. We further demonstrate an actionable dependence of our murine ABC-DLBCL model on BCL2. This BCL2 dependence was also detectable in human ABC-DLBCL cell lines. Moreover, human ABC-DLBCLs displayed increased PD-L1 expression, compared to GCB-DLBCL. In vivo experiments in our ABC-DLBCL model showed that combined venetoclax and RMP1-14 significantly increased the overall survival of lymphoma bearing animals, indicating that this combination may be a viable option for selected human ABC-DLBCL cases harboring MYD88 and BCL2 aberrations.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Lymphoma, Large B-Cell, Diffuse / Myeloid Differentiation Factor 88 Type of study: Prognostic_studies Limits: Animals Language: En Journal: Blood Cancer Discov Year: 2021 Document type: Article Affiliation country: Germany Country of publication: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Lymphoma, Large B-Cell, Diffuse / Myeloid Differentiation Factor 88 Type of study: Prognostic_studies Limits: Animals Language: En Journal: Blood Cancer Discov Year: 2021 Document type: Article Affiliation country: Germany Country of publication: United States