N-myc transgene promotes B lymphoid proliferation, elicits lymphomas and reveals cross-regulation with c-myc.

Abstract

To assess the impact of constitutive N‐myc expression on lymphocytes, we generated lines of transgenic mice bearing the murine N‐myc oncogene coupled to the immunoglobulin heavy chain enhancer (E mu). As in mice carrying an analogous c‐myc construct, E mu‐N‐myc mice exhibit a limited overgrowth of cycling pre‐B cells and eventually succumb to clonal B lymphoid tumours. The endogenous N‐myc and c‐myc alleles are silent in both E mu‐N‐myc and E mu‐myc lymphomas, suggesting that these genes are subject to auto‐ and cross‐regulation. The regulatory interaction and the similar biological effects of N‐myc and c‐myc imply that the two genes perform interchangeable functions in the promotion of cell proliferation.

MYC oncogenes and human neoplastic disease

“…This provided an important in vivo context within which to compare N-myc and L-myc. Rosenbaum et al (1989), Dildrop et al (1989) and Sheppard et al (1998) thus created Em-N-myc transgenic animals and showed that they too develop clonal lymphoid tumors of pre-B and Bcell origin. In the latter case, the disease resembled human follicular lymphoma and followed a more indolent course which may have been attributable to lower levels of transgene expression and/or strain di erences.…”

Transgenic N-myc mouse model for indolent B cell lymphoma: tumor characterization and analysis of genetic alterations in spontaneous and retrovirally accelerated tumors

“…Several factors may contribute to the di erences in disease phenotypes observed with the N-myc transgenes, namely, the use of mouse strains expressing di erent H-2 antigens, the positional e ect or local environment of transgene integration, transgene copy number, strength of their promoter elements and transgene expression levels. The presence of a vigorous SV40 promoter resulted in elevated N-myc expression levels and gave rise to highly malignant lymphosarcomas on the hybrid C57BL6/SJL (H-2b/s) background (Rosenbaum et al, 1989). The C57BL6/SJL lines were maintained by matings of transgenic males to C57BL6/ SJL females, providing an equal genetic representation of C57BL6 and SJL reminiscent of the original embryo genotype.…”

“…Since the sites of transgene insertion have not been reported in any of these studies, no conclusions can be made related to the in¯uences of local chromosomal environment on transgene expression. The unifying features of the aggressive, high-grade transgenic N-myc lymphomas (Rosenbaum et al, 1989;Dildrop et al, 1989) were the high levels of transgene expression noted in tumors and tumor-derived cell lines, and the ability of the tumor cells to adapt stably to growth in vitro. In marked contrast, our Em-N-myc mice exhibited basal level transgene expression and the cells obtained from tumors failed to proliferate in vitro.…”

“…In marked contrast, our Em-N-myc mice exhibited basal level transgene expression and the cells obtained from tumors failed to proliferate in vitro. Rosenbaum et al (1989) reported that mice in two progeny lines developed aggressive lymphosarcomas (one preB cell, the other B cell) due to the expression of an Em-N-myc construct regulated by SV40 promoter sequences and missing nearly all of the 3' untranslated region of N-myc. Transgene expression was 20 times greater than single copy (*basal) gene level of N-myc expression.…”

“…Some of these transgenes contained an Ig heavy chain (HC) gene enhancer and were regulated either by promoter elements of the endogenous N-myc gene or by exogenous SV40 promoter sequences. In studies of progeny lines derived from two founder mice reported by Rosenbaum et al (1989), a murine Em-N-myc transgene, present at 2 ± 5 copies per genome, driven by a strong exogenous promoter and missing nearly all of the 3' untranslated region gave rise to markedly elevated levels of transgenic N-myc mRNA concomitant with downregulation of endogenous N-myc expression and the appearance of highly malignant, widely-disseminated lymphosarcomas. Each progeny line revealed its individual tumor cell type including preB, preB/B and mature B cell, and showed variations in tumor cell type from generation to generation.…”