Dildrop R, Ma A, Zimmerman K, Hsu E, Tesfaye A, DePinho R, Alt F W
Howard Hughes Medical Institute, New York, NY.
EMBO J. 1989 Apr;8(4):1121-8. doi: 10.1002/j.1460-2075.1989.tb03482.x.
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.
我们已构建了转基因小鼠品系，这些品系携带三种不同构建体中的一种，其中鼠源N-myc基因在免疫球蛋白重链转录增强子元件（Eμ-N-myc基因）的控制下表达。Eμ-N-myc转基因在淋巴组织中高水平表达；相应地，许多这些Eμ-N-myc品系可重复性地发生前B淋巴细胞和B淋巴细胞恶性肿瘤。Eμ-N-myc转基因似乎也参与了一只Eμ-N-myc小鼠中发生的T细胞恶性肿瘤的发生。这些肿瘤及其衍生的细胞系表达异常高水平的Eμ-N-myc转基因；其水平与在具有高度扩增的N-myc基因的人类神经母细胞瘤中观察到的水平相当。相比之下，所有Eμ-N-myc细胞系的c-myc RNA序列水平异常低或无法检测到，这与高水平N-myc表达可能参与c-myc基因表达的负性“交叉调节”的可能性一致。我们的研究结果表明，尽管N-myc基因从未与自然发生的B淋巴细胞恶性肿瘤相关联，但N-myc基因的失调表达在B淋巴细胞谱系中具有强大的致癌潜力。我们的结果还在正常细胞和转化细胞中myc基因活性差异的背景下进行了讨论。
