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| Item Type: | Article |
|---|---|
| Title: | B cell-specific conditional expression of Myd88(p.L252P) leads to the development of diffuse large B cell lymphoma in mice |
| Creators Name: | Knittel, G., Liedgens, P., Korovkina, D., Seeger, J.M., Al-Baldawi, Y., Al-Maarri, M., Fritz, C., Vlantis, K., Bezhanova, S., Scheel, A.H., Wolz, O.O., Reimann, M., Möller, P., López, C., Schlesner, M., Lohneis, P., Weber, A.N.R., Trümper, L., Staudt, L.M., Ortmann, M., Pasparakis, M., Siebert, R., Schmitt, C.A., Klatt, A.R., Wunderlich, F.T., Schäfer, S.C., Persigehl, T., Montesinos-Rongen, M., Odenthal, M., Büttner, R., Frenzel, L.P., Kashkar, H. and Reinhardt, H.C. |
| 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. |
| Keywords: | B-Lymphocytes, Diffuse Large B-Cell Lymphoma, Experimental Neoplasms, Missense Mutation, Myeloid Differentiation Factor 88, Neoplastic Cell Transformation, Proto-Oncogene Proteins c-bcl-2, Transgenic Mice, Animals, Mice |
| Source: | Blood |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Volume: | 127 |
| Number: | 22 |
| Page Range: | 2732-2741 |
| Date: | 2 June 2016 |
| Official Publication: | https://doi.org/10.1182/blood-2015-11-684183 |
| PubMed: | View item in PubMed |
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