RAPID INDUCTION OF B-CELL LYMPHOMAS IN MICE CARRYING A HUMAN IGH C-MYCYAC/

Activation of the c-myc proto-oncogene by one of the imnunoglobulin (I g) loci after chromosomal translocation is a consistent feature of Bur kitt's lymphoma. Different subtypes of this tumor vary in the molecula r architecture of the translocation region. In most cases there are no known regulatory elements of the Ig locus neighboring the oncogene an d this considerably obscures the mechanism of its deregulation. In ord er to assess possible oncogene activation signals, we produced an expe rimental translocation region by insertion of a c-myc gene about 50 kb from the IgH intron enhancer in a yeast artificial chromosome (YAC) c ontaining a 220 kb region of the human Ig heavy chain (IgH) locus. Sin gle copy integration of this YAC into the genome of mouse embryonic st em (ES) cells was achieved by spheroplast fusion. Chimeric mice derive d from these ES cells developed monoclonal B-cell lymphomas expressing surface IgM by 8-16 weeks of age. The IgH/c-myc translocus showed dif ferent V(H)DJ(H) rearrangement in almost all tumors without any altera tions of the distance between c-myc and the IgH intron enhancer. This mouse model can be used for the in vivo analysis of c-myc deregulation and the tumor formation capacity of the IgH locus in aberrant rearran gements.