{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T06:24:31Z","timestamp":1791181471382,"version":"4.1.0"},"reference-count":39,"publisher":"Rockefeller University Press","issue":"7","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,7,6]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1084\/jem.20082842","type":"journal-article","created":{"date-parts":[[2009,6,9]],"date-time":"2009-06-09T01:50:13Z","timestamp":1244512213000},"page":"1473-1483","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":84,"title":["Agricultural pesticide exposure and the molecular connection to lymphomagenesis"],"prefix":"10.1084","volume":"206","author":[{"given":"Julie","family":"Agopian","sequence":"first","affiliation":[{"name":"Centre d'Immunologie de Marseille-Luminy, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) U631, Centre National de la Recherche Scientifique UMR6102, Universit\u00e9 de la M\u00e9diterran\u00e9e, 13288 Marseilles, France 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Marc","family":"Navarro","sequence":"additional","affiliation":[{"name":"Centre d'Immunologie de Marseille-Luminy, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) U631, Centre National de la Recherche Scientifique UMR6102, Universit\u00e9 de la M\u00e9diterran\u00e9e, 13288 Marseilles, France 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Claire","family":"Gac","sequence":"additional","affiliation":[{"name":"Groupe R\u00e9gional d'Etudes sur le Cancer EA1772, IFR 146, Centre Fran\u00e7ois Baclesse, 14076 Caen, France 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yannick","family":"Lecluse","sequence":"additional","affiliation":[{"name":"Groupe R\u00e9gional d'Etudes sur le Cancer EA1772, IFR 146, Centre Fran\u00e7ois Baclesse, 14076 Caen, France 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J. Work Environ. Health."},{"key":"2023072917202036200_bib4","doi-asserted-by":"crossref","first-page":"3553","DOI":"10.1182\/blood-2008-08-174839","article-title":"Transformation of follicular lymphoma to diffuse large B-cell lymphoma may occur by divergent evolution from a common progenitor cell or by direct evolution from the follicular lymphoma clone","volume":"113","author":"Carlotti","year":"2009","journal-title":"Blood."},{"key":"2023072917202036200_bib5","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1182\/blood-2005-12-008755","article-title":"Agricultural pesticide use and risk of t(14;18)-defined subtypes of non-Hodgkin lymphoma","volume":"108","author":"Chiu","year":"2006","journal-title":"Blood."},{"key":"2023072917202036200_bib6","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/0092-8674(86)90362-4","article-title":"Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2\/immunoglobulin transcript resulting from the t(14;18) translocation","volume":"47","author":"Cleary","year":"1986","journal-title":"Cell."},{"key":"2023072917202036200_bib7","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1200\/JCO.1996.14.4.1333","article-title":"BCL-2\/JH rearrangements in circulating B cells of healthy blood donors and patients with nonmalignant diseases","volume":"14","author":"Dolken","year":"1996","journal-title":"J. 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Biomarkers Prev."},{"key":"2023072917202036200_bib12","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1182\/blood-2002-05-1537","article-title":"Effect of antiviral treatment in patients with chronic HCV infection and t(14;18) translocation","volume":"102","author":"Giannelli","year":"2003","journal-title":"Blood."},{"key":"2023072917202036200_bib13","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1182\/blood.V84.5.1361.1361","article-title":"A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group","volume":"84","author":"Harris","year":"1994","journal-title":"Blood."},{"key":"2023072917202036200_bib14","doi-asserted-by":"crossref","first-page":"3520","DOI":"10.1182\/blood.V95.11.3520","article-title":"Follicular lymphomas' BCL-2\/IgH junctions contain templated nucleotide insertions: novel insights into the mechanism of t(14;18) translocation","volume":"95","author":"Jager","year":"2000","journal-title":"Blood."},{"key":"2023072917202036200_bib15","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/nri2217","article-title":"Germinal centres: role in B-cell physiology and malignancy","volume":"8","author":"Klein","year":"2008","journal-title":"Nat. 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Med."},{"key":"2023072917202036200_bib18","doi-asserted-by":"crossref","first-page":"2528","DOI":"10.1182\/blood.V85.9.2528.bloodjournal8592528","article-title":"Lymphoma-associated translocation t(14;18) in blood B cells of normal individuals","volume":"85","author":"Limpens","year":"1995","journal-title":"Blood."},{"key":"2023072917202036200_bib19","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/0092-8674(89)90174-8","article-title":"bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation","volume":"57","author":"McDonnell","year":"1989","journal-title":"Cell."},{"key":"2023072917202036200_bib20","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/S0092-8674(00)00078-7","article-title":"Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme","volume":"102","author":"Muramatsu","year":"2000","journal-title":"Cell."},{"key":"2023072917202036200_bib21","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1084\/jem.20012144","article-title":"Activation-induced deaminase (AID)\u2013directed hypermutation in the immunoglobulin Smu region: implication of AID involvement in a common step of class switch recombination and somatic hypermutation","volume":"195","author":"Nagaoka","year":"2002","journal-title":"J. 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Med."},{"key":"2023072917202036200_bib31","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.it.2007.10.005","article-title":"Pathophysiological aspects of memory B-cell development","volume":"29","author":"Roulland","year":"2008","journal-title":"Trends Immunol."},{"key":"2023072917202036200_bib32","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1182\/blood-2007-11-124560","article-title":"S(mu) mutation patterns suggest different progression pathways in follicular lymphoma: early direct or late from FL progenitor cells","volume":"112","author":"Ruminy","year":"2008","journal-title":"Blood."},{"key":"2023072917202036200_bib33","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1002\/j.1460-2075.1988.tb02791.x","article-title":"Alternative promoters and exons, somatic mutation and deregulation of the Bcl-2-Ig fusion gene in lymphoma","volume":"7","author":"Seto","year":"1988","journal-title":"EMBO J."},{"key":"2023072917202036200_bib34","first-page":"3894","article-title":"Expression of activation-induced cytidine deaminase is confined to B-cell non-Hodgkin's lymphomas of germinal-center phenotype","volume":"63","author":"Smit","year":"2003","journal-title":"Cancer Res."},{"key":"2023072917202036200_bib35","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1056\/NEJMcibr067155","article-title":"A closer look at follicular lymphoma","volume":"356","author":"Staudt","year":"2007","journal-title":"N. 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