Targeted overexpression of an activated N-ras gene results in B- and plasma cell lymphoproliferation and cooperates with c-myc to induce fatal B-cell neoplasia

• Published in: Experimental hematology 2011-11, Vol.40 (3), p.216-227
• Main Authors: Linden, Michael A., Kirchhof, Nicole, Carlson, Cathy S., Van Ness, Brian G.
• Format: Article
• Language: English
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2011.11.006

Multiple myeloma (MM) is an incurable malignant expansion of plasma cells in the bone marrow. Although there is no pathognomonic genetic lesion among MM patients, activation of the ras gene has been identified as a common mutation. We have previously described the use of the 3′ kappa immunoglobulin light chain enhancer (3′KE) to target transgenic expression in murine B- and plasma cells, resulting in bcl-X L and c- myc driven murine models of MM. In this report, we characterize the role of activated mutant N- ras in B- and plasma cells in transgenic mice. We constructed transgenic mice that use the 3′KE to direct expression of a mutant activated N- ras . We also crossed the N- ras mice to mice bearing a c- myc transgene to study the cooperative effects of the transgenic constructs. Mice were sacrificed when moribund or at specific time intervals and characterized by serology, light microscopy, and flow cytometry. The transgenic N- ras animals develop B- and plasma cell lymphoproliferation, and aged mice develop immunoglobulinemia, renal hyaline tubular casts, and microscopic foci of abnormal plasma cells in extramedullary sites, including the liver and kidney. Bitransgenic 3′KE/N-Ras V12 x Eμ-c-Myc mice develop fatal B-cell neoplasia with a median survival of 10 weeks. These data indicate that activated N- ras can play a role in B- and plasma cell homeostasis and that activated N-Ras and c-Myc can cooperate to induce B-cell neoplasia.