We have shown that trans-rearrangements between (rather than within) antigen receptor genes are formed by site-specific recombination between variable segments from one immune receptor locus and joining segments from another. We have demonstrated that such events occur in the peripheral T-cells of all normal individuals but are 10-100 times more frequent in the peripheral T-cells of patients with ataxia-telangiectasia (AT). These trans-rearrangements (1) affect and alter the repertoire of immune receptor diversity, (2) suggest that an underlying defect in AT may be chromatin -hyperaccessibility+, and (3) provide a possible screening test for people at increased risk for the development of lymphoid-specific chromosomal translocations, and therefore lymphoid malignancy. We have completed a pilot study of individuals involved in the agriculture industry in which we have demonstrated an acquired transient -AT-like+ picture in individuals exposed to a variety of pesticides and herbicides. We have demonstrated a related increase in Hodgkin+s disease patients receiving chemotherapy, an iatrogenic cancer risk increasing influence. We are in the process of analyzing women involved in the agriculture industry or exposed to well water that might be contaminated by pesticides in a particular Canadian province to determine if this assay correlates with the risk of this population for lymphoid malignancy. We have also studied the effect of a particular agent, 2.4 D on the incidence of these rearrangements in foresters divided into subgroups on the basis of the method of application of this insecticide. While these studies await verification and extension in large scale population-based studies, we have turned to a murine model because it offers more opportunity for performing refined genetics and also for identifying specific instability-inducing agents. We have found that scid mice, if given low dose (100 cGy) total body irradiation within the first 48 hours of life, show a remarkable and profound increase in the number of TCRVG/TCRJB trans-rearrangements when assayed at one to two weeks following the exposure. Underscoring the relevance and predictive value of this assay for trans-rearrangements, all of the mice so irradiated are dead of thymic lymphoma by 20 weeks of age.
| Kirsch, I R; Ried, T (2000) Integration of cytogenetic data with genome maps and available probes: present status and future promise. Semin Hematol 37:420-8 |
| Shou, Y; Martelli, M L; Gabrea, A et al. (2000) Diverse karyotypic abnormalities of the c-myc locus associated with c-myc dysregulation and tumor progression in multiple myeloma. Proc Natl Acad Sci U S A 97:228-33 |
| Tonon, G; Roschke, A; Stover, K et al. (2000) Spectral karyotyping combined with locus-specific FISH simultaneously defines genes and chromosomes involved in chromosomal translocations. Genes Chromosomes Cancer 27:418-23 |
| Kirsch, I R; Green, E D; Yonescu, R et al. (2000) A systematic, high-resolution linkage of the cytogenetic and physical maps of the human genome. Nat Genet 24:339-40 |
