Preferential development of pre-B lymphomas with drastically down-regulated N-myc in the E mu-ret transgenic mice.

We established one transgenic mouse line which developed pre-B leukemic lymphomas by introducing ret cDNA driven by the SV40 promoter and the mouse immunoglobulin (Ig) enhancer. Lymphomas developed not only in the lymph nodes and the spleen but also in the thymus between the ages of 7 and 21 weeks. Analyses of cell surface phenotypes and Ig gene rearrangement revealed that these tumors were surface IgM-B220+ pre-B lymphomas. The rearrangement pattern of the Ig heavy chain locus indicated that the tumor cells were mono- or oligoclonal. Northern blot analysis showed that the ret transgene was expressed at a high level not only in the tumors but also in the prelymphomatous lymphoid tissues. We found that the expression of N-myc was dramatically down-regulated in the tumor cells, while the expression of c-myc was rather stable. Further experiments demonstrated that ret gene product did not directly down-regulate the expression of N-myc in transformed pre-B cell lines by in vitro transfection assay. From these results, we conclude that under the control of Ig enhancer, the ret transgene affected B lymphocytes at the early maturation stage as a prerequisite for transformation, preferentially generating a unique maturation stage of pre-B lymphomas whose N-myc expression was developmentally down-regulated.