B-cell–specific conditional expression of Myd88p.L252P leads to the development of diffuse large B-cell lymphoma in mice

Abstract

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

Biology of CNS lymphoma and the potential of novel agents

“…The significance of this mutation was recently highlighted by the discovery that B-cell–specific conditional expression of MYD88 L265P promotes the development of DLBCL in mice. 12 In addition, mutations involving the immunoreceptor tyrosine-based activation motif (ITAM) of the B-cell antigen receptor–associated protein cluster of differentiation 79B (CD79B) occur in ~40% of PCNSL. Importantly, mutational frequencies for these genes are considerably higher in PCNSL compared with non-CNS, ABC-type large cell lymphoma, in which MYD88 and CD79B mutations are detected by resequencing in ~39% and in ~20% of cases, respectively.…”

Mechanisms of NF-κB deregulation in lymphoid malignancies

“…3) [113]. Importantly, B-cell specific mutation of endogenous murine MYD88 at L252P (equivalent to human L265P) is sufficient to induce lymphoproliferation and clonal lymphomas with morphological and immunophenotypical characteristics of ABC DLBCL [115]. Whereas in a previous mouse model expression of constitutively active IKK␤ and simultaneous disruption of BLIMP1 was required for ABC DLBCL like development [82], in this case a single MYD88 mutation was sufficient to trigger lymphomagenesis.…”

Murine models of germinal center derived-lymphomas

“…In mice, activating mutations in Myd88 ( Myd88 L252P ) induced by Cd19-Cre or Aid-Cre develop tumors (CD138 − Bcl6 − Irf4 + ) sharing characteristics with human ABC DLBCL [38]. Further, non-canonical NF-κB signaling during lymphomagenesis is highlighted in hyper-immunized mice overexpressing Nik and Bcl6 (IμBcl6; Nik ;Cγ1-Cre) [39].…”