title: B-cell-specific conditional expression of Myd88p.L252P leads to the development of diffuse large B-cell lymphoma in mice.
abstract: The adaptor protein MYD88 is critical for relaying activation of Toll-like receptor signaling to NF-κB activation. MYD88 mutations, particularly the p.L265P mutation, have been described in numerous distinct B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL). Twenty-nine percent of activated B-cell-type DLBCL (ABC-DLBCL), which is characterized by constitutive activation of the NF-κB pathway, carry the p.L265P mutation. In addition, ABC-DLBCL frequently displays focal copy number gains affecting BCL2 Here, we generated a novel mouse model in which Cre-mediated recombination, specifically in B cells, leads to the conditional expression of Myd88(p.L252P) (the orthologous position of the human MYD88(p.L265P) mutation) from the endogenous locus. These mice develop a lymphoproliferative disease and occasional transformation into clonal lymphomas. The clonal disease displays the morphologic and immunophenotypical characteristics of ABC-DLBCL. Lymphomagenesis can be accelerated by crossing in a further novel allele, which mediates conditional overexpression of BCL2 Cross-validation experiments in human DLBCL samples revealed that both MYD88 and CD79B mutations are substantially enriched in ABC-DLBCL compared with germinal center B-cell DLBCL. Furthermore, analyses of human DLBCL genome sequencing data confirmed that BCL2 amplifications frequently co-occurred with MYD88 mutations, further validating our approach. Finally, in silico experiments revealed that MYD88-mutant ABC-DLBCL cells in particular display an actionable addiction to BCL2. Altogether, we generated a novel autochthonous mouse model of ABC-DLBCL that could be used as a preclinical platform for the development and validation of novel therapeutic approaches for the treatment of ABC-DLBCL.
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany;
authors.forename: Gero
authors.initials: G
authors.lastname: Knittel
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany;
authors.forename: Paul
authors.initials: P
authors.lastname: Liedgens
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany;
authors.forename: Darya
authors.initials: D
authors.lastname: Korovkina
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany; Institute for Microbiology and Hygiene, and.
authors.forename: Jens M
authors.initials: JM
authors.lastname: Seeger
authors.affiliation: Department of Radiology, Medical Faculty, University Hospital of Cologne, Cologne, Germany;
authors.forename: Yussor
authors.initials: Y
authors.lastname: Al-Baldawi
authors.affiliation: Max Planck Institute for Metabolism Research, Cologne, Germany;
authors.forename: Mona
authors.initials: M
authors.lastname: Al-Maarri
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany;
authors.forename: Christian
authors.initials: C
authors.lastname: Fritz
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany;
authors.forename: Katerina
authors.initials: K
authors.lastname: Vlantis
authors.affiliation: Institute of Pathology, University Hospital of Cologne, Cologne, Germany; N.N. Blokhin Russian Cancer Research Center, Moscow, Russia;
authors.forename: Svetlana
authors.initials: S
authors.lastname: Bezhanova
authors.affiliation: Institute of Pathology, University Hospital of Cologne, Cologne, Germany;
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Scheel
authors.affiliation: Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany;
authors.forename: Olaf-Oliver
authors.initials: OO
authors.lastname: Wolz
authors.affiliation: Department of Hematology/Oncology, Charité-University Medical Center, Berlin, Germany;
authors.forename: Maurice
authors.initials: M
authors.lastname: Reimann
authors.affiliation: Institute of Pathology, Medical Faculty of Ulm University, Ulm, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: Möller
authors.affiliation: Institute for Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Kiel, Germany;
authors.forename: Cristina
authors.initials: C
authors.lastname: López
authors.affiliation: Department of Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany;
authors.forename: Matthias
authors.initials: M
authors.lastname: Schlesner
authors.affiliation: Department of Pathology, Charité-University Medical Center, Berlin, Germany;
authors.forename: Philipp
authors.initials: P
authors.lastname: Lohneis
authors.affiliation: Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany;
authors.forename: Alexander N R
authors.initials: AN
authors.lastname: Weber
authors.affiliation: Department of Hematology and Oncology, Georg-August University, Goettingen, Germany;
authors.forename: Lorenz
authors.initials: L
authors.lastname: Trümper
authors.affiliation: Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
authors.affiliation: Institute of Pathology, University Hospital of Cologne, Cologne, Germany;
authors.forename: Monika
authors.initials: M
authors.lastname: Ortmann
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany;
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
authors.affiliation: Institute for Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Kiel, Germany;
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.affiliation: Department of Hematology/Oncology, Charité-University Medical Center, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany;
authors.forename: Clemens A
authors.initials: CA
authors.lastname: Schmitt
authors.affiliation: Institute for Clinical Chemistry.
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Klatt
authors.affiliation: Max Planck Institute for Metabolism Research, Cologne, Germany;
authors.forename: F Thomas
authors.initials: FT
authors.lastname: Wunderlich
authors.affiliation: Institute of Pathology, University Hospital of Cologne, Cologne, Germany;
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Schäfer
authors.affiliation: Department of Radiology, Medical Faculty, University Hospital of Cologne, Cologne, Germany;
authors.forename: Thorsten
authors.initials: T
authors.lastname: Persigehl
authors.affiliation: Institute of Neuropathology, and.
authors.forename: Manuel
authors.initials: M
authors.lastname: Montesinos-Rongen
authors.affiliation: Institute of Pathology, University Hospital of Cologne, Cologne, Germany; Center of Integrated Oncology, University Hospital of Cologne, Cologne, Germany; and.
authors.forename: Margarete
authors.initials: M
authors.lastname: Odenthal
authors.affiliation: Institute of Pathology, University Hospital of Cologne, Cologne, Germany; Center of Integrated Oncology, University Hospital of Cologne, Cologne, Germany; and Center of Molecular Medicine, University of Cologne, Cologne, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Büttner
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany; Center of Integrated Oncology, University Hospital of Cologne, Cologne, Germany; and.
authors.forename: Lukas P
authors.initials: LP
authors.lastname: Frenzel
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany; Institute for Microbiology and Hygiene, and Center of Molecular Medicine, University of Cologne, Cologne, Germany.
authors.forename: Hamid
authors.initials: H
authors.lastname: Kashkar
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany; Center of Integrated Oncology, University Hospital of Cologne, Cologne, Germany; and Center of Molecular Medicine, University of Cologne, Cologne, Germany.
authors.forename: H Christian
authors.initials: HC
authors.lastname: Reinhardt
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D053594:Myeloid Differentiation Factor 88 / Q000096:biosynthesis* / Q000235:genetics; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D019253:Proto-Oncogene Proteins c-bcl-2; C052617:Bcl2 protein, mouse