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

SUNG SUP PARK; JOONG SU KIM; Nicole MCNEIL; Thomas RIED; J. Frederic MUSHINSKI; Herbert C MORSE; Siegfried JANZ; Lino TESSAROLLO; James D OWENS; LIANGPING PENG; SEONG SU HAN; SEUNG TAE CHUNG; Ted A TORREY; Wan C CHEUNG; Roberto D POLAKIEWICZ

doi:10.1158/0008-5472.CAN-04-0268

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

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

SUNG SUP PARK, JOONG SU KIM, Nicole MCNEIL, Thomas RIED, J. Frederic MUSHINSKI, Herbert C MORSE, Siegfried JANZ, Lino TESSAROLLO, James D OWENS, LIANGPING PENG, …

Cancer research (Chicago, Ill.), Vol.65(4), pp.1306-1315

2005

DOI: 10.1158/0008-5472.CAN-04-0268

PMID: 15735016

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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.

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Details

Title: Subtitle: Insertion of c-Myc into Igh induces B-cell and plasma-cell neoplasms in mice
Creators: SUNG SUP PARK - Laboratory of Genetics,, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, United States
JOONG SU KIM - Laboratory of Genetics,, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, United States
Nicole MCNEIL - Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, United States
Thomas RIED - Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, United States
J. Frederic MUSHINSKI - Laboratory of Genetics,, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, United States
Herbert C MORSE - Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, United States
Siegfried JANZ - Laboratory of Genetics,, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, United States
Lino TESSAROLLO - Laboratory of Genetics,, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, United States
James D OWENS - Laboratory of Genetics,, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, United States
LIANGPING PENG - Laboratory of Genetics,, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, United States
SEONG SU HAN - Laboratory of Genetics,, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, United States
SEUNG TAE CHUNG - Laboratory of Genetics,, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, United States
Ted A TORREY - Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, United States
Wan C CHEUNG - Laboratory for Neural Development Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States
Roberto D POLAKIEWICZ - Cell Signaling Technology, Beverly, Massachusetts, United States
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.65(4), pp.1306-1315
DOI: 10.1158/0008-5472.CAN-04-0268
PMID: 15735016
NLM abbreviation: Cancer Res
ISSN: 0008-5472
eISSN: 1538-7445
Publisher: American Association for Cancer Research
Language: English
Date published: 2005
Academic Unit: Stead Family Department of Pediatrics; Pathology
Record Identifier: 9984083260802771

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