Sequencing studies of Diffuse Large B Cell Lymphoma (DLBCL) have identified hundreds of recurrently altered genes. However, it remains largely unknown whether and how these mutations may contribute to lymphomagenesis, either individually or in combination. Existing strategies to address this problem predominantly utilize cell lines, which are limited by their initial characteristics and subsequent adaptions to prolongedin vitroculture. Here, we describe a novel co-culture system that enables theex vivoexpansion and viral transduction of primary human germinal center B cells. The incorporation of CRISPR/Cas9 technology enables high-throughput functional interrogation of genes recurrently mutated in DLBCL. Using a backbone ofBCL2with eitherBCL6orMYCwe have identified co-operating oncogenes that promote growth and survival, or even full transformation into synthetically engineered models of DLBCL. The resulting tumors can be expanded and sequentially transplantedin vivo, providing a scalable platform to test putative cancer genes and for the creation of mutation-directed, bespoke lymphoma models.