| Help | About | Contact Us

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.

Expression

Publication --> Expression annotations

Other

34 Authors

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

15 Bio Entities

0 Expression

Questions? Comments? Click here!

MouseMine is a collaboration between MGI at The Jackson Laboratory and the InterMine project at the Cambridge Systems Biology Centre. MouseMine is funded through a grant from the NIH/NHGRI.The Jackson Laboratory makes no representation about the suitability or accuracy of this software or data for any purpose, and makes no warranties, either express or implied, including merchantability and fitness for a particular purpose or that the use of this software or data will not infringe any third party patents, copyrights, trademarks, or other rights. the software and data are provided "as is". This software and data are provided to enhance knowledge and encourage progress in the scientific community and are to be used only for research and educational purposes. Any reproduction or use for commercial purpose is prohibited without the prior express written permission of the Jackson Laboratory.

Your name:
Your email address:
Subject:
Message:	---- Current page: ---- /mousemine/report.do?id=74185033

MouseMine