Novel targeted deregulation of c-Myc cooperates with Bcl-XL to cause plasma cell neoplasms in mice
Wan Cheung Cheung, … , Roberto D. Polakiewicz, Siegfried Janz
Wan Cheung Cheung, … , Roberto D. Polakiewicz, Siegfried Janz
Published June 15, 2004
Citation Information: J Clin Invest. 2004;113(12):1763-1773. https://doi.org/10.1172/JCI20369.
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Article Oncology

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

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

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Figure 4

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Proliferation and apoptosis in lymph node follicles of 8-week-old Myc, M...
Proliferation and apoptosis in lymph node follicles of 8-week-old Myc, Myc/Bcl-XL, and Bcl-XL mice compared with normal nontransgenic littermates. (A) Sections of a peripheral lymph node containing two follicles. Follicular B cells undergoing proliferation or apoptosis are immunostained (brown spots) for phosphohistone H3 or activated caspase-3, respectively (original magnification, ∞40). The images are ordered from top to bottom according to the apparent turnover of follicular B cells, which was highest in the Myc mice and lowest in the Bcl-XL mice. (B) The result of the microscopic enumeration of proliferating B cells (black bars) and dying B cells (gray bars) in lymph node follicles. Three lymph nodes of each mouse strain were evaluated to determine mean values and SDs of the mean.