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B cell-specific conditional expression of Myd88(p.L252P) leads to the development of diffuse large B cell lymphoma in mice

Official URL:https://doi.org/10.1182/blood-2015-11-684183
PubMed:View item in PubMed
Creators Name:Knittel, G. and Liedgens, P. and Korovkina, D. and Seeger, J.M. and Al-Baldawi, Y. and Al-Maarri, M. and Fritz, C. and Vlantis, K. and Bezhanova, S. and Scheel, A.H. and Wolz, O.O. and Reimann, M. and Moeller, P. and Lopez, C. and Schlesner, M. and Lohneis, P. and Weber, A.N.R. and Truemper, L. and Staudt, L.M. and Ortmann, M. and Pasparakis, M. and Siebert, R. and Schmitt, C.A. and Klatt, A.R. and Wunderlich, F.T. and Schaefer, S.C. and Persigehl, T. and Montesinos-Rongen, M. and Odenthal, M. and Buettner, R. and Frenzel, L.P. and Kashkar, H. and Reinhardt, H.C.
Journal Title:Blood
Journal Abbreviation:Blood
Page Range:2732-2741
Date:2 June 2016
Abstract:The adaptor protein MYD88 is critical to relay activation of Toll-like receptor signaling to NF-{kappa}B activation.MYD88 mutations, particularly the p.L265P mutation, have been described in numerous distinct B cell malignancies, including diffuse large B cell lymphoma (DLBCL). 29% of activated B cell (ABC)-type DLBCL, which is characterized by constitutive activation of the NF-{kappa}B 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 animals develop a lympho-proliferative disease, and occasional transformation into clonal lymphomas. The clonal disease displays morphological and immunophenotypical characteristics of ABC-DLBCL. Lymphomagenesis can be accelerated by crossing in a further novel allele, which mediates conditional overexpression ofBCL2 Cross-validation experiments in human DLBCL samples revealed that bothMYD88andCD79Bmutations are substantially enriched in ABC-DLBCL, compared to germinal center B cell DLBCL. Furthermore, analyses of human DLBCL genome sequencing data confirmed that BCL2 amplifications frequently co-occur with MYD88 mutations, further validating our approach. Lastly,in silicoexperiments revealed that particularly MYD88-mutant ABC-DLBCL cells display an actionable addiction to BCL2. Altogether, we generated a novel autochthonous mouse model of ABC-DLBCL, which could be used as a preclinical platform for the development and validation of novel therapeutic approaches for the treatment of ABC-DLBCL.
Publisher:American Society of Hematology (U.S.A.)
Item Type:Article

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