Published online
doi:10.1084/jem.2043iti3
The Journal of Experimental Medicine, Vol. 204, No. 3, 454-
The Rockefeller University Press, 0022-1007 $30.00
© Bashyam
Switching defects
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Activated B cell–like (ABC) lymphomas have a higher rate of intraswitch deletions compared with other lymphomas.
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Switching from one antibody isotype to another is a risky business that involves altering and cleaving DNA. B cell lymphomas that are stuck in the riskiest stage suffer repeated mutations and insertions that may further drive oncogenesis, according to Lenz et al. on page 633.
Mature B cells switch from producing IgM to other antibody isotypes during their response to antigen. This process, known as class switch recombination (CSR), is initiated by an enzyme called activation-induced cytidine deaminase (AID). Modification of DNA bases by AID within a so-called switch region leads to DNA cleavage. An intervening sequence is looped out, and two cleaved switch regions are ligated together to create a new gene encoding a new antibody isotype.
The group had previously found that the activated B cell–like (ABC) lymphomas had high expression of AID compared with certain other lymphoma subtypes. They now find that almost two-thirds of the ABC lymphoma cells tested have abnormal CSR events and almost half have internal deletions in a switch region. The switch regions contained as many as 19 independent deletions interspersed with mutations at AID hot spots. The changes could be organized into lineage models, suggesting an ongoing process of aberrant processing.
AID expression is normally a transient phenomenon that occurs as B cells mature. ABC lymphomas, however, are stuck at an intermediate phase of B cell maturation. One consequence is sustained high levels of AID expression. This by itself does not appear to be sufficient to explain the phenotype—another lymphoma subtype expresses almost as much AID but suffers fewer problems with CSR. The AID overexpression in ABC lymphomas may be combined with a defect (as yet hypothetical) in proteins that complete CSR. The frustrated machinery would turn on its own target sites, leading to deletions and mutations rather than a clean class switch.
In one lymphoma, DNA fragments from other chromosomes were inserted into the deletion sites, highlighting the danger inherent in aberrant class switch recombination. Translocations involving cancer-causing genes were also observed, suggesting that defective switching might sometimes further drive oncogenesis in these B cell lymphomas. 
Hema Bashyam
hbashyam{at}rockefeller.edu
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