The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20082842
The Journal of Experimental Medicine, Vol. 206, No. 7, 1473-1483
The Rockefeller University Press, 0022-1007 $30.00
© Agopian et al.
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BRIEF DEFINITIVE REPORT

 Agricultural pesticide exposure and the molecular connection to lymphomagenesis

Julie Agopian1, Jean-Marc Navarro1, Anne-Claire Gac2, Yannick Lecluse2, Mélanie Briand2, Pierre Grenot1, Pascal Gauduchon2, Philippe Ruminy3, Pierre Lebailly2, Bertrand Nadel1, and Sandrine Roulland1

1 Centre d'Immunologie de Marseille-Luminy, Institut National de la Santé et de la Recherche Médicale (INSERM) U631, Centre National de la Recherche Scientifique UMR6102, Université de la Méditerranée, 13288 Marseilles, France
2 Groupe Régional d'Etudes sur le Cancer EA1772, IFR 146, Centre François Baclesse, 14076 Caen, France
3 INSERM U918, Groupe d'étude des Proliférations Lymphoïdes, IFRMP23, 76038 Rouen, France

CORRESPONDENCE Bertrand Nadel: nadel{at}ciml.univ-mrs.fr OR Pierre Lebailly: p.lebailly{at}baclesse.fr

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.

J. Agopian and J.-M. Navarro contributed equally to this paper.

Abbreviations used: AID, activation-induced cytidine deaminase; CSR, class switch recombination; FL, follicular lymphoma; GC, germinal center; HI, healthy individuals; ICV, intraclonal variation; LR-PCR, long-range PCR; mbr, major breakpoint region; NHL, non-Hodgkin's lymphoma; SHM, somatic hypermutation; SR-PCR, short-range PCR.

© 2009 Agopian et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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