B-cell tumorigenesis in mice carrying a yeast artificial chromosome-based immunoglobulin heavy/c-myc translocus is independent of the heavy chain intron enhancer (E mu)

We have used YAC (yeast artificial chromosome) technology to create targe t ranslocation regions where the c-myc proto-oncogene is coupled to the core region of the human immunoglobulin heavy chain (IgH) locus (from VH2-5 thro ugh to C delta), Chimeric mice were obtained from embryonic stem cells carr ying a single copy of the 240-kb IgH/c-myc translocation region. B-cell tum origenesis occurs in the translocus mice, even when the entire E mu intron enhancer region between the joining segments and switch mu is deleted. This demonstrates that as yet unidentified regulatory elements in the IgH locus , independent from the known enhancers, are sufficient to cause B-cell spec ific activation of c-myc after translocation. The phenotype of tumors from IgHc-myc YAC transgenic mice with or without E mu (B220(+), IgM(+)/IgD(+)) is reminiscent of Burkitt's lymphoma. A rapidly expanding abnormal B-cell p opulation is present at birth and accumulates in bone marrow, periphery, an d spleen, well before discrete tumor establishment. Molecular analysis iden tified a clonal origin, with rearrangement of one mouse heavy chain allele retained in tumor cells from different sites, whereas subsequent rearrangem ents of heavy or light chain loci can be diverse. These mice routinely deve lop mature B-cell tumors early in life and may provide an invaluable resour ce of a B-cell lymphoma model.