Published online November 12, 2007
doi:10.1084/jem.20070882
The Journal of Experimental Medicine, Vol. 204, No. 12, 2989-3001
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Kovalchuk et al.
AID-deficient Bcl-xL transgenic mice develop delayed atypical plasma cell tumors with unusual Ig/Myc chromosomal rearrangements
Alexander L. Kovalchuk1,4,
Wendy duBois1,
Elizabeth Mushinski1,
Nicole E. McNeil2,
Carsten Hirt1,3,
Chen-Feng Qi4,
Zhaoyang Li4,
Siegfried Janz1,5,
Tasuku Honjo6,
Masamichi Muramatsu7,
Thomas Ried2,
Timothy Behrens8, and
Michael Potter1
1 Laboratory of Cancer Biology and Genetics, 2 Genetics Branch, Cancer Genomics Section, National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD 20892
3 Ernst-Moritz-Arndt University, D-17487 Greifswald, Germany
4 Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852
5 Department of Pathology, University of Iowa, Carver Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242
6 Department of Immunology and Genomic Medicine, Kyoto University, Graduate School of Medicine, Kyoto 606-8501, Japan
7 Department of Molecular Genetics, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8640, Japan
8 Genentech, Inc., South San Francisco, CA 94080
CORRESPONDENCE Michael Potter:potter{at}helix.nih.gov
Activation-induced cytidine deaminase (AID) is required for immunoglobulin (Ig) class switch recombination and somatic hypermutation, and has also been implicated in translocations between Ig switch regions and c-Myc in plasma cell tumors in mice. We asked if AID is required for accelerated tumor development in pristane-treated Bcl-xL transgenic BALB/c mice deficient in AID (pBxAicda–/–). pBxAicda–/– mice developed tumors with a lower frequency (24 vs. 62%) and a longer mean latency (108 vs. 36 d) than AID-sufficient mice. The tumors appeared in oil granuloma tissue and did not form ascites. By interphase fluorescence in situ hybridization, six out of nine pBxAicda–/– primary tumors had T(12;15) and one had T(6;15) chromosomal translocations. Two tumors were transplantable and established as stable cell lines. Molecular and cytogenetic analyses showed that one had an unusual unbalanced T(12;15) translocation, with IgH Cµ and Pvt-1 oriented head to tail at the breakpoint, resulting in an elevated expression of c-Myc. In contrast, the second was T(12;15) negative, but had an elevated N-Myc expression caused by a paracentric inversion of chromosome 12. Thus, novel mechanisms juxtapose Ig and Myc-family genes in AID-deficient plasma cell tumors.
Abbreviations used: aCGH, array comparative genomic hybridization; AID, activation-induced cytidine deaminase; BAC, bacterial artificial chromosome; CNS, central nervous system; DSB, double-strand break; FISH, fluorescence in situ hybridization; qPCR, quantitative PCR; SKY, spectral karyotyping.
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