title: Insertion of c-Myc into Igh induces B-cell and plasma-cell neoplasms in mice.
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.
authors.affiliation: Laboratory of Genetics, Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
authors.forename: Sung Sup
authors.initials: SS
authors.lastname: Park
authors.forename: Joong Su
authors.initials: JS
authors.lastname: Kim
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.forename: James D
authors.initials: JD
authors.lastname: Owens
authors.forename: Liangping
authors.initials: L
authors.lastname: Peng
authors.forename: Seong Su
authors.initials: SS
authors.lastname: Han
authors.forename: Seung
authors.initials: S
authors.lastname: Tae Chung
authors.forename: Ted A
authors.initials: TA
authors.lastname: Torrey
authors.forename: Wan C
authors.initials: WC
authors.lastname: Cheung
authors.forename: Roberto D
authors.initials: RD
authors.lastname: Polakiewicz
authors.forename: Nicole
authors.initials: N
authors.lastname: McNeil
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
authors.forename: J Frederic
authors.initials: JF
authors.lastname: Mushinski
authors.forename: Herbert C
authors.initials: HC
authors.lastname: Morse
authors.forename: Siegfried
authors.initials: S
authors.lastname: Janz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology; D002051:Burkitt Lymphoma / Q000235:genetics / Q000473:pathology; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D004195:Disease Models, Animal; D016147:Genes, Tumor Suppressor / Q000502:physiology; D016259:Genes, myc / Q000235:genetics*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D010954:Plasmacytoma / Q000235:genetics* / Q000473:pathology; D017354:Point Mutation; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic; D019076:Transgenes; D014178:Translocation, Genetic / Q000235:genetics*
chemical_list: D007143:Immunoglobulin Heavy Chains