Signalling through the phosphoinositide 3-kinase (PI3K) pathway is critical for immune cell development and function. Patients with a gain of function mutation in PI3Kδ, called Activated PI3Kδ syndrome (APDS) commonly develop autoimmunity, lymphoproliferation, and lymphoma. PIK3CD is also among the most commonly mutated genes in Diffuse Large B cell lymphoma (DLBCL). The most commonly studied mouse model of DLBCL was generated by knocking a BCL6 transgene into the Igμ locus (μHABCL-6Tg). Our lab has generated a mouse model of APDS in which a hyperactivated PI3Kδ (p110δE1020K) was knocked in constitutively or selectively in B cells or T cells. We crossed p110δE1020K knockin-mice with μHABCL-6Tg. μHABCL-6Tg single transgenic mice develop a disease reminiscent of DLBCL, but with up to a year’s latency, whereas histological examination revealed lymphoplasia in some p110δE1020K mice and most p110δE1020K-μHABCL-6Tg mice after 15-20 weeks. Tumour surveillance plays an important role in mouse models of DLBCL. To explore the development of lymphoma in the absence of T cells in the microenvironment, I transferred purified B cells from the p110δE1020K, μHABCL-6Tg or double mutant mice into Rag2−/− mice which lack mature B cells and T cells. Aggressive B cell lymphoma developed after 10-15 weeks in Rag2−/− mice that received B cells from p110δE1020K x μHABCL-6Tg B cells but not in mice that received B cells from p110δE1020K or μHABCL-6Tg single transgenic mice. Moreover, I was able to generate B cell lines (called Fly cell lines) from each of the transgenic donors in the Rag2−/− strains, but not from wild-type donors. When I transferred double mutant Fly cells into Rag2−/− mice, these mice showed signs of full hind limb and tail paralysis. Histological examination of several tissues from these mice revealed the presence of pleomorphic cells in bone marrow and epidural space of the spinal cord, compressing spinal cord in places and dramatically affecting the Central Nervous System, causing the clinical signs associated with metastatic epidural and spinal cord lymphoma. These data highlight a synergy between BCL6 and PI3Kδ in B cell transformation, with hyperactive PI3Kδ more oncogenic than deregulated BCL6. Both genes are highly involved in the germinal centre reaction, modulating the transcription of genes required for cell activation and differentiation. These mice will prove useful for assessing the role of both PI3Kδ and BCL6 in transformed B cells as well as in the role of PI3Kδ in T cells that can either promote or suppress B cell transformation. Moreover, the technique and cell lines developed can be used to study the mechanisms of CNS, spinal cord and bone marrow invasion and of the immunomodulatory effects of T cells.