Insertion of c-Myc into Igh induces B-cell and plasma-cell neoplasms in mice

Sup Park Sung, Su Kim Joong, Lino Tessarollo, James D. Owens, Liangping Peng, Su Han Seong, Tae Chung Seung, Ted A. Torrey, Wan C. Cheung, Roberto D. Polakiewicz, Nicole McNeil, Thomas Ried, J. Frederic Mushinski, Herbert C. Morse, Siegfried Janz

Research output: Contribution to journalArticlepeer-review

99 Scopus citations

Abstract

We used gene targeting in mice to insert a His6-tagged mouse c-Myc cDNA, MycHis, head to head into the mouse immunoglobulin heavy-chain locus, Igh, just 5′ of the intronic enhancer, Eμ. The insertion of MycHis 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 MycHis, 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-cel lymphomas contained a BL-typical point mutation in the amino-terminal transactivation domain of MycHis, 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 p19Arf-Mdm2- p53 tumor suppressor axis, an important pathway for Myc-dependent apoptosis. We conclude that MycHis insertion into Igh predictably induces B-cell and plasma-cell tumors in mice, providing a valuable mouse model for understanding the transformation-inducing consequences of the MYC/Myc-activating endemic Burkitt lymphoma t(8;14)/plasmacytoma T(12;15) translocation.

Original languageEnglish (US)
Pages (from-to)1306-1315
Number of pages10
JournalCancer Research
Volume65
Issue number4
DOIs
StatePublished - Feb 15 2005

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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