Abstract
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 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.
Highlights
Reciprocal chromosomal translocations that activate the cellular oncogene MYC are widely accepted as the initiating events in the natural history of human endemic Burkitt lymphoma, an aggressive form of mature, postgerminal center, non-HodgkinNote: S.S
Because onset and level of MycHis expression during B-cell development are likely to play an important role in determining incidence and types of lymphomas that might arise in iMycEA mice, we assessed the expression of MycHis protein in lysates of fluorescence-activated cell-sorting (FACS)-sorted B cells at different maturation stages using immunoblotting with antibody to the His6 tag (Fig. 2A)
Gene insertion was used to recreate as a germ line mutation in mice the MYC/Myc-activating Igh translocations seen in human endemic Burkitt lymphomas and certain mouse plasmacytomas
Summary
Reciprocal chromosomal translocations that activate the cellular oncogene MYC are widely accepted as the initiating events in the natural history of human endemic Burkitt lymphoma, an aggressive form of mature, postgerminal center, non-Hodgkin. Note: S.S. Park, J.S. Kim, and L. Tessarollo contributed to this article and are sharing first authorship. S.S. Park and J.S. Kim are currently in Laboratory of Functional Proteomics, Korea Research Institute of Bioscience and Biotechnology, Taejon, Korea
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