The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20081007
The Journal of Experimental Medicine, Vol. 205, No. 9, 1949-1957
The Rockefeller University Press, 0022-1007 $30.00
© Takizawa et al.
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BRIEF DEFINITIVE REPORT

 AID expression levels determine the extent of cMyc oncogenic translocations and the incidence of B cell tumor development

Makiko Takizawa1, Helena Tolarová1, Zhiyu Li1, Wendy Dubois2, Susan Lim1, Elsa Callen3, Sonia Franco4, Maria Mosaico5, Lionel Feigenbaum5, Frederick W. Alt4, André Nussenzweig3, Michael Potter2, and Rafael Casellas1

1 Genomic Integrity and Immunity, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD 20892
2 Laboratory of Genetics and 3 Experimental Immunology, National Cancer Institute (NCI), NIH, Bethesda, MD 20892
4 Children's Hospital, CBR Institute for Biomedical Research, and Howard Hughes Medical Institute, Boston, MA 02115
5 Laboratory Animal Science Program, SAIC, NCI, NIH, Frederick, MD 21702

CORRESPONDENCE Michael Potter: potter{at}helix.nih.gov OR Rafael Casellas: casellar{at}mail.nih.gov

Immunoglobulin (Ig) isotype switching is a recombination event that changes the constant domain of antibody genes and is catalyzed by activation-induced cytidine deaminase (AID). Upon recruitment to Ig genes, AID deaminates cytidines at switch (S) recombination sites, leading to the formation of DNA breaks. In addition to their role in isotype switching, AID-induced lesions promote Igh-cMyc chromosomal translocations and tumor development. However, cMyc translocations are also present in lymphocytes from healthy humans and mice, and thus, it remains unclear whether AID directly contributes to the dynamics of B cell transformation. Using a plasmacytoma mouse model, we show that AID+/– mice have reduced AID expression levels and display haploinsufficiency both in the context of isotype switching and plasmacytomagenesis. At the Ig loci, AID+/– lymphocytes show impaired intra- and inter-switch recombination, and a substantial decrease in the frequency of S mutations and chromosomal breaks. In AID+/– mice, these defects correlate with a marked decrease in the accumulation of B cell clones carrying Igh-cMyc translocations during tumor latency. These results thus provide a causality link between the extent of AID enzymatic activity, the number of emerging Igh-cMyc–translocated cells, and the incidence of B cell transformation.


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