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

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Abstract

Deregulated expression of both Myc and Bcl-XL are consistent features of human plasma cell neoplasms (PCNs). To investigate whether targeted expression of Myc and Bcl-XL 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, MycHis, into the mouse Ig heavy-chain Cα locus. We also generated Bcl-XL transgenic mice that contain a multicopy Flag-tagged mouse Bcl-xFlag transgene driven by the mouse Ig κ light-chain 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 (4 of 43, 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 contained elevated amounts of MycHis and Bcl-XLFlag proteins compared with the plasma cells that accumulated in large numbers in young tumor-free Myc/Bcl-XL mice. Our findings demonstrate 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 some features of human multiple myeloma.

Authors

Wan Cheung Cheung, Joong Su Kim, Michael Linden, Liangping Peng, Brian Van Ness, Roberto D. Polakiewicz, Siegfried Janz