We have continued our studies on the pathogenesis of mouse B cell and plasma cell neoplasms that are induced by chromosomal translocations T(12;15) that result in the deregulated expression of the proto-oncogene Myc. The T(12;15) translocation is the direct counterpart of the MYC-activating t(8;14)(q24;q32) translocation most commonly seen in human Burkitt lymphoma (BL). In the past fiscal year we have made significant advances in three project areas: We furthered our understanding of the origin of the T(12;15) translocation by demonstrating that aberrant immunoglobulin (Ig) class switch recombination (CSR) facilitates translocation by an indirect mechanism: transpositon of Ig heavy-chain (Igh) sequences to Myc. Five Igh transposons containing the intronic heavy-chain enhancer Em and a truncated switch m region (Sm) were found inserted in the first intron of Myc in B-cell clones of IL-6 transgenic BALB/c mice. In two cases Em/Sm transposition primed Myc to get involved in trans-chromosomal CSR to Cg1, leading to T(12;15). Our model proposes that Em/Sm transposition to Myc sensitizes Myc to undergo T(12;15) translocation, which, in turn, juxtaposes the oncogene to the heavy-chain Ca enhancer. The final outcome is a mode of Myc deregulation that is conducive to B cell and plasma cell tumor formation in mice. Using gene insertion in transgenic mice, we have mimicked three different states of the human BL t(8;14) translocation and the homologous mouse plasmacytoma (PCT) T(12;15) translocation. We refer to the newly developed gene-insertion strains as iMyc mice. The mice are prone to neoplastic B cell and plasma cell development, including lymphoblastic B-cell lymphoma (LBL), diffuse large B cell lymphoma (DLBCL) and plasmacytoma (PCT). Together these are tumors of mature B cells that are highly relevant for B-cell derived non-Hodgkin's lymphomas in humans. Our most recent unpublished work has shown that approximately 50% of LBL that arise in the iMyc-Em mice exhibit distortions in the Myc-Arf-Mdm2-p53 tumor suppressor axis. Some tumors without interruptions of this axis over-express survivin, presumably to counterbalance Myc-dependent apoptosis. Constitutive NF-kB signaling due to PI3K-Akt activation appears to play an important role in tumor progression. These findings suggest that the iMyc model system affords an excellent opportunity to design and test new approaches for the treatment and prevention of human B cell and plasma cell tumors. Since deregulated expression of MYC and BCL-XL are consistent features of human plasma cell neoplasms (PCN), we decided to investigate whether targeted expression of Myc and Bcl-XL in mouse plasma cells might lead to an improved model of human PCN. To that end, we crossed our newly developed iMyc-Ca mice with newly generated BCL-XL transgenics that contain a mouse BCL-XL transgene driven by the mouse Igk 3' enhancer. Single transgenic BCL-XL mice remained tumor free by 380 days of age, whereas single transgenic Myc mice developed B-cell tumors infrequently (9.3%). In contrast, double transgenic Myc/BCL-XL mice developed plasma cell tumors with short onset (135 days on average) and full penetrance (100% tumor incidence). These tumors produced monoclonal Ig, infiltrated the bone marrow and caused, in some cases, osteolytic lesions with pathological bone fractures. We thus demonstrated that the enforced expression of Myc and BCL-XL by Ig enhancers with peak activity in plasma cells generates a mouse model of human PCN that recapitulates key features of human multiple myeloma.
