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

Abstract

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 (E mu‐N‐myc genes). High‐level expression of the E mu‐N‐myc transgenes occurred in lymphoid tissues; correspondingly, many of these E mu‐N‐myc lines reproducibly developed pre‐B‐ and B‐lymphoid malignancies. The E mu‐N‐myc transgene also appeared to participate in the generation of a T cell malignancy that developed in one E mu‐N‐myc mouse. These tumors and cell lines adapted from them expressed exceptionally high levels of the E mu‐N‐myc transgene; the levels were comparable to those observed in human neuroblastomas with highly amplified N‐myc genes. In contrast, all of the E mu‐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.

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

“…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. Dildrop et al (1989) introduced several Nmyc fusion gene constructs with either exogenous or endogenous promoter elements into C57BL6/CBA (H2b/k) mice. These tumor-bearing mouse lines were maintained by backcrossing to C57BL6 females which provided a greater contribution of the C57BL6 genotype and H-2b haplotype with each subsequent generation.…”

“…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.…”

“…Since transgene copy numbers were low (2 ± 5) in these two mouse lines, the elevated levels of transgene expression may have been due, in part, to the in¯uence of a strong exogenous regulatory element. In the studies reported by Dildrop et al (1989) three constructs were used: ESN: driven by SV40 promoter sequences, EN: similar to the Em-N-myc construct we have used including a nearly intact 3' untranslated region and the endogenous N-myc promoter elements, and EVN: murine N-myc regulated by Ig HC gene enhancer and promoter sequences. Transgene expression levels in stable cell lines derived from resultant lymphoblastoid tumors (preB, mature B, and variant of B cell types) were reported to be 50 times greater than basal level expression.…”

“…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. In studies reported by Dildrop et al (1989) two progeny mouse lines that bore an N-myc transgene (EN) regulated by endogenous promoter elements and present at 10 copies per genome developed aggressive preB and B cell lymphoblastoid tumors. Another progeny mouse line which was established with an SV40 promoter-regulated N-myc (ESN) present at ®ve copies per genome caused high-grade lymphoblastoid tumors following delayed onset.…”