B cell-specific conditional expression of Myd88(p.L252P) leads to the development of diffuse large B cell lymphoma in mice
Autor/innen
- G. Knittel
- P. Liedgens
- D. Korovkina
- J.M. Seeger
- Y. Al-Baldawi
- M. Al-Maarri
- C. Fritz
- K. Vlantis
- S. Bezhanova
- A.H. Scheel
- O.O. Wolz
- M. Reimann
- P. Möller
- C. López
- M. Schlesner
- P. Lohneis
- A.N.R. Weber
- L. Trümper
- L.M. Staudt
- M. Ortmann
- M. Pasparakis
- R. Siebert
- C.A. Schmitt
- A.R. Klatt
- F.T. Wunderlich
- S.C. Schäfer
- T. Persigehl
- M. Montesinos-Rongen
- M. Odenthal
- R. Büttner
- L.P. Frenzel
- H. Kashkar
- H.C. Reinhardt
Journal
- Blood
Quellenangabe
- Blood 127 (22): 2732-2741
Zusammenfassung
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.