V(D)J RECOMBINASE & CHROMOSOME TRANSLOCATION IN LYMPHOMA

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Lymphomas are a significant cause of morbidity and mortality in humans. Whereas protooncogenes involved in lymphoma formation have been identified, the complete genetic pathways resulting in lymphomas remain elusive. The majority of human lymphomas have been noted to have chromosomal translocations, and most of these involve the immunoglobulin (Ig) loci. Evidence suggests that V(D)J recombination, which represents a regulated form of genetic instability, may mediate chromosomal translocations resulting in the deregulated expression of genes affecting lymphocyte growth or survival. The fact that lymphomagenic events are rare underscores the existence of cellular mechanisms to prevent aberrant V(D)J recombination. Mice with mutations in the SCID gene are severely limited in their ability to effectively repair coding ends to generate functional antigen receptors and have defective double strand DNA break repair, indicating that the SCID gene product plays a role in both V(D)J recombination and double strand DNA break repair. SCID x p53 -/- mice uniformly develop disseminated B cell lymphomas, which we have discovered contain recurrent t(12;15) involving the IgH locus. We have, thus, defined a genetic pathway leading to a particular chromosomal translocation, possibly involving the V(D)J recombinase mechanism. We propose to use FISH analysis to map and clone the chromosome 12 translocation breakpoint, examining the sequence for characteristics of V(D)J recombination and identifying potential oncogenes. Using a mouse model, we propose to investigate whether absence of V(D)J recombination suppresses the development of aggressive pro-B cell lymphomas. The long term goal of this project will be to study the role of V(D)J recombination as a potential genetic pathway for chromosomal translocations leading to the development of lymphomas. Such insight may further the understanding of lymphomagenesis and may help in the development of novel anti-tumor strategies.