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B-cell-specific conditional expression of Myd88p.L252P leads to the development of diffuse large B-cell lymphoma in mice.
- Source :
-
Blood [Blood] 2016 Jun 02; Vol. 127 (22), pp. 2732-41. Date of Electronic Publication: 2016 Apr 05. - Publication Year :
- 2016
-
Abstract
- The adaptor protein MYD88 is critical for relaying activation of Toll-like receptor signaling to NF-κB 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-κB 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.
- Subjects :
- Animals
B-Lymphocytes pathology
Cell Transformation, Neoplastic genetics
Cell Transformation, Neoplastic pathology
Humans
Lymphoma, Large B-Cell, Diffuse genetics
Lymphoma, Large B-Cell, Diffuse pathology
Mice
Mice, Transgenic
Myeloid Differentiation Factor 88 genetics
Neoplasms, Experimental genetics
Neoplasms, Experimental pathology
Proto-Oncogene Proteins c-bcl-2 biosynthesis
Proto-Oncogene Proteins c-bcl-2 genetics
B-Lymphocytes metabolism
Cell Transformation, Neoplastic metabolism
Lymphoma, Large B-Cell, Diffuse metabolism
Mutation, Missense
Myeloid Differentiation Factor 88 biosynthesis
Neoplasms, Experimental metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 127
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 27048211
- Full Text :
- https://doi.org/10.1182/blood-2015-11-684183