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

First Author	Knittel G	Year	2016
Journal	Blood	Volume	127
Issue	22	Pages	2732-41
PubMed ID	27048211	Mgi Jnum	J:232098
Mgi Id	MGI:5776023	Doi	10.1182/blood-2015-11-684183
Citation	Knittel G, et al. (2016) B-cell-specific conditional expression of Myd88p.L252P leads to the development of diffuse large B-cell lymphoma in mice. Blood 127(22):2732-41

abstractText

The adaptor protein MYD88 is critical for relaying activation of Toll-like receptor signaling to NF-kappaB 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-kappaB 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.

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34 Authors

German International Cancer Genome Consortium Molecular Mechanisms in Malignant Lymphoma by Sequencing Project Consortium.,
Möller P,
Fritz C,
Ortmann M,
Reimann M,
Kashkar H,
Büttner R,
Frenzel LP,
Al-Maarri M,
Weber AN,
Staudt LM,
Lohneis P,
Schäfer SC,
López C,
Liedgens P,
Montesinos-Rongen M,
Wunderlich FT,
Wolz OO,
Siebert R,
Bezhanova S,
Reinhardt HC,
Odenthal M,
Korovkina D,
Persigehl T,
Schmitt CA,
Scheel AH,
Schlesner M,
Vlantis K,
Trümper L,
Al-Baldawi Y,
Knittel G,
Pasparakis M,
Seeger JM,
Klatt AR

15 Bio Entities

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