Recently, two large-scale genomic studies identified a set of clusters of diffuse large B-cell lymphoma (DLBCL) based on analysis of recurrent genomic alterations. Here, cluster 5 (C5, Chapuy et al.) and MCD (Schmitz et al.), enriched for mutations of MYD88, overexpression of BCL2 and SPIB and loss of PRDM1, share a particularly poor prognosis, emphasizing the demand for novel treatment strategies for these patients. We generated two mouse models of C5/MCD DLBCL by crossing a Prdm1flox and a Rosa26LSL.Spib.IRES.GFP allele into our previously published Myd88c-p.L252P/wt; Rosa26LSL.BCL2.IRES.GFP/wt; Cd19Cre/wt DLBCL background. Here, we are employing our novel mouse models as preclinical tools to develop novel targeted strategies for the treatment of C5/MCD DLBCL in vivo. Additionally, we are performing an in vivo insertional mutagenesis screen to identify molecular vulnerabilities cooperating with oncogenic Myd88 in DLBCL lymphomagenesis. This project will help to pave the way towards a targeted treatment of genetically defined cases of DLBCL.