Novel targeted deregulation of c-Myc cooperates with Bcl-XL to cause plasma cell neoplasms in mice

Deregulated expression of both Myc and Bcl-X-L are consistent features of human plasma cell neoplasms (PCNs). To investigate whether targeted expression of Myc and BCl-X-L in mouse plasma cells might lead to an improved model of human PCN, we generated Myc transgenics by inserting a single-copy histidine-tagged mouse Myc gene, Myc(His), into the mouse Ig heavy-chain Calpha locus. We also generated Bcl-X-L transgenic mice that contain a multicopy Flag-tagged mouse Bcl-x(Flag) transgene driven by the mouse Ig K fight-chain 3' enhancer. Single-transgenic Bcl-X-L mice remained tumor free by 380 days of age, whereas single-transgenic Myc mice developed B cell tumors infrequently (4 of 43, 9.3%). In contrast, double-transgenic Myc/Bcl-X-L 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 contained elevated amounts of Myc(His) and Bcl-X-L(Flag) proteins compared with the plasma cells that accumulated in large numbers in young tumor-free Myc/Bcl-X-L mice. Our findings demonstrate that the enforced expression of Myc and Bcl-X-L by Ig enhancers with peak activity in plasma cells generates a mouse model of human PCN that recapitulates some features of human multiple myeloma.