IgH enhancer-mediated deregulation of N-myc gene expression in transgenic mice: Generation of lymphoid neoplasias that lack c-myc expression

We have generated transgenic mouse lines that carry one of three different constructs in which the murine N-myc gene is expressed under the control of the immunoglobulin heavy chain transcriptional enhancer element (Eμ-N-myc genes). High-level expression of the Eμ-N-myc transgenes occurred in lymphoid tissues; correspondingly, many of these Eμ-N-myc lines reproducibly developed pre-B- and B-lymphoid malignancies. The Eμ-N-myc transgene also appeared to participate in the generation of a T cell malignancy that developed in one Eμ-N-myc mouse. These tumors and cell lines adapted from them expressed exceptionally high levels of the Eμ-N-myc transgene; the levels were comparable to those observed in human neuroblastomas with highly amplified N-myc genes. In contrast, all of the Eμ-N-myc cell lines had exceptionally low or undetectable levels of the c-myc RNA sequences, consistent with the possibility that high-level N-myc expression can participate in the negative 'cross-regulation' of c-myc gene expression. Our findings demonstrate that deregulated expression of the N-myc gene has potent oncogenic potential within the B-lymphoid lineage despite the fact that the N-myc gene has never been implicated in naturally occurring B-lymphoid malignancies. Our results also are discussed in the context of differential myc gene activity in normal and transformed cells.