Journal
BLOOD
Volume 127, Issue 22, Pages 2732-2741Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2015-11684183
Keywords
-
Categories
Funding
- Volkswagenstiftung (Lichtenberg Program)
- Deutsche Forschungsgemeinschaft [KFO-286, KA 2853/4-1, SFB-685]
- Deutsche Jose Carreras Leukamie Stiftung [R12/26]
- Marga und Walter Boll Stiftung [210-05-13]
- Helmholtz-Gemeinschaft (Preclinical Comprehensive Cancer Center)
- Else Kroner-Fresenius Stiftung [EKFS-2014-A06]
- Marlene Porsche Foundation for Cancer Prevention
- Else-Ubelmesser Stiftung (Juniorprofessoren-Programn)
- Deutsche Krebshilfe [111724]
- German Ministry of Science and Education in the framework of the International CancerGenome Consortium Molecular Mechanisms in Malignant Lymphoma by Sequencing Project [01KU1002A-J]
Ask authors/readers for more resources
The adaptor protein MYD88 is critical for relaying 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). Twenty-nine percent of activated B-cell-type DLBCL (ABC-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 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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available