An Autochthonous Mouse Model of Myd88- and BCL2-Driven Diffuse Large B-cell Lymphoma Reveals Actionable Molecular Vulnerabilities

  • Blood Cancer Discov. 2021 Jan;2(1):70-91. doi: 10.1158/2643-3230.BCD-19-0059.
Ruth Flümann  #  1  2  3  4 ,  Tim Rehkämper  #  1  2  3  4 ,  Pascal Nieper  #  1  2  3  4 ,  Pauline Pfeiffer  1  2  3  4 ,  Alessandra Holzem  1  2  3  4 ,  Sebastian Klein  5 ,  Sanil Bhatia  6 ,  Moritz Kochanek  1  2  3  4 ,  Ilmars Kisis  1  2  3  4 ,  Benedikt W Pelzer  1  2  3  4 ,  Heinz Ahlert  6 ,  Julia Hauer  7  8 ,  Alexandra da Palma Guerreiro  1  2  4 ,  Jeremy A Ryan  9 ,  Maurice Reimann  10 ,  Arina Riabinska  1  2  3  4 ,  Janica Wiederstein  4 ,  Marcus Krüger  4 ,  Martina Deckert  2  11 ,  Janine Altmüller  12 ,  Andreas R Klatt  13 ,  Lukas P Frenzel  1  2  4 ,  Laura Pasqualucci  14 ,  Wendy Béguelin  15 ,  Ari M Melnick  15 ,  Sandrine Sander  16 ,  Manuel Montesinos-Rongen  2  11 ,  Anna Brunn  2  11 ,  Philipp Lohneis  2  3  5 ,  Reinhard Büttner  2  3  5 ,  Hamid Kashkar  3  4  17 ,  Arndt Borkhardt  6 ,  Anthony Letai  9 ,  Thorsten Persigehl  2  18 ,  Martin Peifer  2  3  19 ,  Clemens A Schmitt  10  20 ,  Hans Christian Reinhardt  #  21 ,  Gero Knittel  #  1  2  3  4
Affiliations
  • 1. University of Cologne, Faculty of Medicine and University Hospital Cologne, Clinic I of Internal Medicine, Cologne, Germany.
  • 2. Center for Integrated Oncology, University of Cologne, Cologne, Germany.
  • 3. Center for Molecular Medicine, University of Cologne, Cologne, Germany.
  • 4. Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • 5. Faculty of Medicine and University Hospital Cologne, Institute of Pathology, University of Cologne, Cologne, Germany.
  • 6. Medical Faculty, Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • 7. Department of Pediatrics, Pediatric Hematology and Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
  • 8. National Center for Tumor Diseases (NCT), Dresden, Germany.
  • 9. Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • 10. Charité Universitätsmedizin Berlin, Medical Department of Hematology, Oncology and Tumor Immunology, and Molekulares Krebsforschungszentrum - MKFZ, Virchow Campus, Berlin, Germany.
  • 11. Faculty of Medicine and University Hospital Cologne, Institute of Neuropathology, University of Cologne, Cologne, Germany.
  • 12. Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
  • 13. Faculty of Medicine and University Hospital Cologne, Institute of Clinical Chemistry, University of Cologne, Cologne, Germany.
  • 14. Department of Pathology and Cell Biology, Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.
  • 15. Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, New York.
  • 16. Adaptive Immunity and Lymphoma Group, German Cancer Research Center/National Center for Tumor Diseases Heidelberg, Heidelberg, Germany.
  • 17. Faculty of Medicine and University Hospital Cologne, Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.
  • 18. Faculty of Medicine and University Hospital Cologne, Department of Radiology and Interventional Radiology, University of Cologne, Cologne, Germany.
  • 19. Department of Translational Genomics, University of Cologne, Cologne, Germany.
  • 20. Kepler Universitätsklinikum, Medical Department of Hematology and Oncology, Johannes Kepler University, Linz, Austria.
  • 21. Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University Duisburg-Essen, German Cancer Consortium (DKTK Partner Site Essen), Essen, Germany. [email protected].
  • # Contributed equally.
PMID: 33447829 DOI: 10.1158/2643-3230.BCD-19-0059
Abstract

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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