Agricultural Pesticide Use  and the T(14;18) Connection to Lymphomagenesis

Agricultural pesticide use has been repeatedly, but not consistently, associated with risk of non-Hodgkin lymphoma (NHL). Over the past years, it has become clear that NHL heterogeneity is setting many hurdles to this connection and that pertinent bio-markers must be identified according to malignant subtypes. Among those, t(14;18) translocation constitutes the early and promoting event of a cascade of causative effects leading to Follicular Lymphoma (FL): ectopic BCL2 expression leads to the rescue, accumulation, and developmental block of germinal center (GC) B-cells; there, protracted AID activity would favor the occurrence of complementary oncogenic hits and malignant progression, which arise from mistakes during somatic hypermutation (SHM) and class-switch recombination (CSR) processes. Although the significance of t(14;18) in blood from healthy individuals is yet unclear, evidence for a higher prevalence has been reported among farmers occupationally exposed to pesticides. Furthermore, recent findings have established that pesticide exposure is significantly associated with risk of t(14;18)+ NHL but not with t(14;18)-negative cases, suggesting that pesticides may act through a t(14;18)-dependant pathway. To get molecular insights into this connection, we followed and compared the status and clonal evolution of t(14;18)+ cells over a median of 9 years in blood samples issued from a cohort of farmers exposed to pesticides (n=112) with those of non-farmer controls (n=25). We report here that exposed individuals exhibit a much higher increase of t(14;18) frequency in blood, and that this increase result far less from a genotoxic effect of pesticides than from an immunogenic effect leading to an extensive clonal expansion of activated t(14;18)+ B cells. Strikingly, we demonstrate that such clones recapitulate the hallmark features of developmentally blocked FL cells as they 1) express high levels of BCL2/JH fusion transcripts; 2) retain the CD10 surface expression normally lost upon GC exit; and 3) sustain constitutive AID activity with the most advanced ones bearing, unexpectedly, early stigmata of AID-mediated genomic instability. Altogether these results show that expanded t(14;18)+ clones in farmers exposed to pesticides constitute bona fide FL precursors standing at various stages of tumor progression and support the notion of a direct connection between t(14;18) frequency in blood and malignant progression that could be could helpful in the identification of individuals at “high” risk for transformation to overt FL.