Insertion of c- Myc into Igh Induces B-Cell and Plasma-Cell Neoplasms in Mice

作者：Sung Sup Park, Joong Su Kim, Lino Tessarollo, James D. Owens, Liangping Peng, Seong Su Han, Seung Tae Chung, Ted Albert Torrey, Wan Cheung Cheung, Roberto D. Polakiewicz, Nicole E. McNeil, Thomas Ried, J. Frederic Mushinski, Herbert C. Morse, Siegfried Janz · 发表于：Cancer Research · 年份：2005 · DOI：10.1158/0008-5472.can-04-0268 · 被引用次数：114 · 研究领域：Lymphoma Diagnosis and Treatment、Multiple Myeloma Research and Treatments、Chronic Lymphocytic Leukemia Research

We used gene targeting in mice to insert a His(6)-tagged mouse c-Myc cDNA, Myc(His), head to head into the mouse immunoglobulin heavy-chain locus, Igh, just 5' of the intronic enhancer, Emu. The insertion of Myc(His) mimicked both the human t(8;14)(q24;q32) translocation that results in the activation of MYC in human endemic Burkitt lymphomas and the homologous mouse T(12;15) translocation that deregulates Myc in certain mouse plasmacytomas. Beginning at the age of 6 months, Myc(His) transgenic mice developed B-cell and plasma neoplasms, such as IgM(+) lymphoblastic B-cell lymphomas, Bcl-6(+) diffuse large B-cell lymphomas, and CD138(+) plasmacytomas, with an overall incidence of 68% by 21 months. Molecular studies of lymphoblastic B-cell lymphoma, the most prevalent neoplasm (50% of all tumors), showed that the lymphomas were clonal, overexpressed Myc(His), and exhibited the P2 to P1 promoter shift in Myc expression, a hallmark of MYC/Myc deregulation in human endemic Burkitt lymphoma and mouse plasmacytoma. Only 1 (6.3%) of 16 lymphoblastic B-cell lymphomas contained a BL-typical point mutation in the amino-terminal transactivation domain of Myc(His), suggesting that most of these tumors are derived from naive, pregerminal center B cells. Twelve (46%) of 26 lymphoblastic B-cell lymphomas exhibited changes in the p19(Arf)-Mdm2-p53 tumor suppressor axis, an important pathway for Myc-dependent apoptosis. We conclude that Myc(His) insertion into Igh predictably induces B-cell a...