Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 206, Issue 7, Pages 1473-1483Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20082842
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Funding
- Institut National du Cancer (INCa) [PL06-010]
- Fondation pour la Recherche Medicale (FRM) [INE2003114116]
- Association pour la Recherche sur le Cancer [3618/6974]
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Centre National de la Recherche Scientifique
- Ligue Nationale Contre le Cancer (comite de la Manche)
- Conseil General du Calvados
- Fondation Weisbren Benenson
- Union des Industries de la Protection des Plantes
- Universite de Caen Basse-Normandie
- FRM
- Contrat d'Interface INSERM/AP-H pitaux de Marseille
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The t(14;18) translocation constitutes the initiating event of a causative cascade leading to follicular lymphoma (FL). t(14;18) translocations are present in blood from healthy individuals, but there is a trend of increased prevalence in farmers exposed to pesticides, a group recently associated with higher risk of t(14;18)(+) non-Hodgkin's lymphoma development. A direct connection between agricultural pesticide use, t(14;18) in blood, and malignant progression, however, has not yet been demonstrated. We followed t(14;18) clonal evolution over 9 yr in a cohort of farmers exposed to pesticides. We show that exposed individuals bear particularly high t(14;18) frequencies in blood because of a dramatic clonal expansion of activated t(14;18)+ B cells. We further demonstrate that such t(14;18)+ clones recapitulate the hallmark features of developmentally blocked FL cells, with some displaying aberrant activation-induced cytidine deaminase activity linked to malignant progression. Collectively, our data establish that expanded t(14;18)+ clones constitute bona fide precursors at various stages of FL development, and provide a molecular connection between agricultural pesticide exposure, t(14;18) frequency in blood, and clonal progression.
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