Agricultural pesticide exposure and the molecular connection to lymphomagenesis.
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.
Agopian
Julie
J
Centre d'Immunologie de Marseille-Luminy, Institut National de Santé et de Recherche Médicale (INSERM) U631, Centre National de Recherche Scientifique UMR6102, Université de Méditerranée, 13288 Marseilles, France.
Navarro
Jean-Marc
JM
Gac
Anne-Claire
AC
Lecluse
Yannick
Y
Briand
Mélanie
M
Grenot
Pierre
P
Gauduchon
Pascal
P
Ruminy
Philippe
P
Lebailly
Pierre
P
Nadel
Bertrand
B
Roulland
Sandrine
S
D000328:Adult; D000382:Agricultural Workers' Diseases / Q000139:chemically induced / Q000235:genetics; D016175:B-Lymphocyte Subsets / Q000502:physiology; D001483:Base Sequence; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008224:Lymphoma, Follicular / Q000139:chemically induced / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016273:Occupational Exposure; D010575:Pesticides / Q000009:adverse effects*; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D014178:Translocation, Genetic
D010575:Pesticides; D019253:Proto-Oncogene Proteins c-bcl-2