Pesticide exposure may contribute to cancer by causing genetic mutations during B cell development. On page 1473, Agopian et al. show that pesticides also increase the rate of precancerous B cell proliferation.
Follicular lymphoma is a B cell cancer characterized by a translocation event that occurs as activated B cells undergo AID-driven diversification of their antibody genes in germinal centers (GCs). This translocation, known as t(14;18), links the gene encoding the pro-survival protein BCL2 to the heavy chain locus (IgH) resulting in aberrant BCL2 expression and cell survival. These translocations can also be found in healthy individuals, indicating that additional cancer-causing events are required to cause disease.
This group previously found that farmers exposed to pesticides have increased numbers of t(14;18)-positive B cells in circulation. And pesticide exposure has been associated with increased risk of developing t(14;18)-positive follicular lymphomas. But exactly how pesticides promote lymphoma was unclear.
By following the same group of pesticide-exposed farmers over a decade, the authors now find that pesticide-exposed farmers accumulated t(14;18)-positive B cells faster than their nonexposed neighbors. The t(14;18)-positive cells were mainly clones of a few types, however, which indicated that pesticides were promoting B cell expansion more than they were directly causing DNA damage. How pesticides trigger proliferation remains unknown.
Whether from pesitcide-exposed or unexposed individuals, the circulating t(14:18)-positive B cells derived from GC—as indicated by ongoing AID activity and expression of the GC marker CD10—and constituted bona fide precursors of follicular lymphoma cells. The continuous AID activity correlated with numbers of translocation-containing B cells, providing a clue about how the rapidly proliferating cells may parlay disease. Subsequent mutations triggered by AID-driven breaks and misrepair could result in lymphoma. In future surveys, the authors hope to pinpoint what puts certain t(14;18)-bearing individuals at greater risk for developing cancer.