Key Points• B-cell-specific expression of Myd88 p.L252P leads to the development of DLBCL in mice.• The Myd88 p.L252P mutation cooperates with BCL2 amplifications in ABC-DLBCL lymphomagenesis in vivo.The adaptor protein MYD88 is critical for relaying activation of Toll-like receptor signaling to NF-kB 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-kB 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 cooccurred 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. (Blood. 2016;127(22):2732-2741

No abstract

No abstract

No abstract

Владимирович-врач-уролог, соискатель лаборатории клинической биохимии 1 Короткова Екатерина Андреевнаканд. биол. наук, ст. науч. сотр., лаборатория клинической биохимии 1 Бежанова Светлана Дмитриевнааспирант отдела патологической анатомии опухолей человека 1 Морозов Алексей Андреевич-врачуролог, отделение урологии 2 Алферов Александр Андреевичаспирант лаборатории клинической биохимии 1 Казанцева Ирина Александровнад-р мед. наук, профессор, вед. науч. сотр., патологоанатомическое отделение 2 Кушлинский Николай Евгеньевичд-р мед. наук, профессор, членкорреспондент РАН, заведующий лабораторией клинической биохимии 1