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B-cell–specific conditional expression of Myd88p.L252P leads to the development of diffuse large B-cell lymphoma in mice

2016; Elsevier BV; Volume: 127; Issue: 22 Linguagem: Inglês

10.1182/blood-2015-11-684183

1528-0020

Gero Knittel, Paul Liedgens, Darya Korovkina, Jens M. Seeger, Yussor Al-Baldawi, Mona Al-Maarri, Christian Fritz, Katerina Vlantis, S. D. Bezhanova, Andreas H. Scheel, Olaf‐Oliver Wolz, Maurice Reimann, Peter Möller, Cristina López, Matthias Schlesner, Philipp Lohneis, Alexander N.R. Weber, Lorenz Trümper, Louis M. Staudt, Monika Ortmann, Manolis Pasparakis, Reiner Siebert, Clemens A. Schmitt, Andreas R. Klatt, F. Thomas Wunderlich, Stephan Schäfer, Thorsten Persigehl, Manuel Montesinos‐Rongen, Margarete Odenthal, Reinhard Büttner, Lukas P. Frenzel, Hamid Kashkar, Hans Christian Reinhardt,

Lymphoma Diagnosis and Treatment

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.