Illegitimate V(D)J rearrangement in ã-irradiation induced T cell lymphoma in newborn scid mice

grantor: University of TorontoThe production of DNA double strand breaks during V(D)J recombination, makes developing lymphocytes particularly susceptible to neoplasia. Severe combined immunodeficient (scid) mice inefficiently ligate free coding ends generated during V(D)J recombination due to a mutation in the catalytic subunit of DNA-dependent protein kinase (DNA-PK$\sb{cs}).$ Treatment of newborn scid mice with low dose (100 cGy) $\gamma$-irradiation restores V(D)J rearrangement at multiple TcR loci and results in the universal development of T cell lymphoma. In this study, we used a genetic approach to determine that V(D)J rearrangement played an obligate role in radiation-induced lymphoma in scid mice. We also present evidence of abnormal V(D)J rearrangement in irradiated newborn scid (IRNB-SCID) T cell lines. Our results collectively indicate that sequence specific breaks made during V(D)J rearrangement are essential for radiation-induced lymphomagenesis in scid mice, and that mutations accumulated during attempted TcR$\beta$ locus rearrangement may contribute to the invariant outgrowth of thymic lymphoma.M.Sc