Insertion of c-Myc into Igh induces B-cell and plasma-cell neoplasms in mice.
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.
Park
Sung Sup
SS
Laboratory of Genetics, Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Kim
Joong Su
JS
Tessarollo
Lino
L
Owens
James D
JD
Peng
Liangping
L
Han
Seong Su
SS
Tae Chung
Seung
S
Torrey
Ted A
TA
Cheung
Wan C
WC
Polakiewicz
Roberto D
RD
McNeil
Nicole
N
Ried
Thomas
T
Mushinski
J Frederic
JF
Morse
Herbert C
HC
Janz
Siegfried
S
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*
D007143:Immunoglobulin Heavy Chains