DISCOVERIES
Missteps by Immune Cells, Even When Mature, May Slip Toward Cancer
If antibody-producing B cells are the weapons factories of the immune system, then V(D)J recombination is the first step of the assembly line. This process, which breaks, rearranges, and rejoins segments of DNA called variable, diversity, and joining regions, endows antibodies with a near-infinite variety of molecular warheads. This is how B cells defend humans against invading pathogens.
Fred Alt
Sometimes, however, V(D)J recombination mistakenly joins two different
chromosomes together, and if this translocation turns on genes that help
the cell to grow unchecked, a B cell lymphoma, or tumor, will result.
Now a new study has settled longstanding questions about V(D)J recombination during B cell development and the role it plays in chromosomal translocations. The findings, published July 9 in Nature by a team from Children’s Hospital Boston, the Immune Disease Institute, Brigham and Women’s Hospital, and the National Cancer Institute represent an important advance in understanding the causes of lymphoma.
For years, scientists have known that V(D)J recombination occurs during a B cell’s early development in the bone marrow. But it was unclear whether V(D)J recombination continued to operate in mature B cells residing in “peripheral” immune system organs such as the spleen and lymph nodes. To answer this question, the researchers, led by first author Jing H. Wang, an HMS instructor in pediatrics at IDI, studied B cells in a mouse model. Using a technique they had previously developed, the researchers bred mice to contain splenic B cells incapable of rejoining chromosomes broken during V(D)J recombination. Then they observed the B cell chromosomes through 3-D fluorescent in situ hybridization (FISH), an imaging technique made possible by advanced confocal microscopy. They saw an unusually high number of breaks and translocations in the immunoglobulin lambda light chain gene, a telltale sign of B cells attempting peripheral V(D)J recombination.
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“Understanding the cells and basic mechanisms that underlie these lymphomas is an important step to developing therapies.” —Fred Alt |
The researchers also found that the translocations occurred more often between areas on chromosomes that were frequently broken and physically close to each other. This included cancer genes such as c-myc, which is commonly translocated in B cell tumors. Before this study, chromosomal translocations were thought to occur very rarely, but those that did appear in tumors presumably conferred a survival advantage to the cell. Yet, according to Frederick Alt, a Howard Hughes investigator and the senior author on the study, the new observations suggest that translocations might instead arise from hyperactive translocation mechanisms in tumor cells or their precursors.
“It is too early to say how the findings will affect treatment methods for lymphoma,” Alt said. “However, understanding the cells and basic mechanisms that underlie these lymphomas is an important step to developing therapies.”
Wang, Alt, and their team have begun follow-up experiments to explore how peripheral V(D)J recombination contributes to normal B cell function, as well as to further analyze how gene organization in the nucleus leads to chromosomal translocations.
Students may contact Frederick Alt at alt@enders.tch.harvard.edu for more information.
Conflict Disclosure: The authors declare no conflicts of interest.
Funding Sources: The National Institutes of Health, Leukemia and Lymphoma Society of America, National Cancer Institute, and Howard Hughes Medical Institute; the content of the work is the responsibility solely of the authors.