PF508 AUTOCHTHONOUS MOUSE MODELS OF MYD88 P.L265P ‐ AND BCL2‐DRIVEN DIFFUSE LARGE B CELL LYMPHOMA

Background: There are several recurrent mutations in DLBCL leading to the constitutive activation of NF‐kB, frequently by activating the BCR and TLR pathways (mostly via mutations in CD79B and MYD88 , respectively), or by the loss of a negative feedback loop mediated by the loss of TNFAIP3 . Aims: Here, we aimed to generate novel mouse models of human DLBCL to investigate the role of the most recurrent genetic alterations affecting MYD88 , CD79B , TNFAIP3 and BCL2 in lymphomagenesis in vivo . Methods: We generated a novel mouse model, in which Cre‐mediated recombination leads to the conditional expression of Myd88 p.L252P (the orthologue of the human MYD88 p.L265P mutation) from the endogenous locus. We combined this Myd88 allele (abbr. M) with a BCL2 overexpression allele (abbr. B) and both alleles were activated B cell specifically with CD19:Cre (abbr. C). The effects of these mutations in vivo were carefully characterized. Additionally, we generated a conditional Cd79b p.Y195H allele and also obtained a previously published Tnfaip3 fl allele to model the loss of Tnfaip3 in DLBCL. Results: MBC animals showed elevated levels of self‐reactive antibodies. Immunization experiments revealed that Myd88 p.L252P and BCL2 overexpression cooperate in generating exaggerated antibody responses to exogenous antigen. Ultimately, these animals develop clonal tumors which resemble features of ABC DLBCL histologically and transcriptionally. They were exquisitely sensitive to inhibition of BCL2 in vitro and in vivo . MBC tumors expressed PD‐L1 at elevated levels compared to Eμ:Myc driven lesions. Anti‐PD1 antibody treatment had a stabilizing effect on tumor growth and resulted in a survival benefit. We successfully crossed our novel Cd79b p.Y195H allele into our MBC background to generate a mouse model of human DLBCL with oncogenic CD79B . Additionally, we generated a mouse model of TNFAIP3 ‐deficient lymhpoma by crossing the Tnfaip3 fl allele into our MBC background. Summary/Conclusion: Taken together, we established a Myd88 p.L252P driven mouse model for B cell lymphoma which shares many features with human ABC DLBCL. These tumors are sensitive to inhibition of BCL2 by ABT‐199 and respond to immune checkpoint blockade by anti‐PD1 treatment, suggesting these treatments as potential new strategies in the therapy of a subset of DLBCL patients. Additionally, we are currently investigating a novel conditional Cd79b p.Y195H allele and are modelling the loss of Tnfaip3 in DLBCL using a previously published allele.