Long-range effects of retroviral insertion on c-myb:: Overexpression may be obscured by silencing during tumor growth in vitro
Long-range effects of retroviral insertion on c-myb:: Overexpression may be obscured by silencing during tumor growth in vitro
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DOI：
10.1128/jvi.77.2.1059-1068.2003
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发表时间：
2003-01-01
影响因子：
5.4
通讯作者：
Neil, JC
中科院分区：
文献类型：
--
作者：
Hanlon, L;Barr, NI;Neil, JC
c-myb癌基因是禽类和哺乳动物造血系统肿瘤中逆转录病毒激活的常见靶基因。虽然插入可以直接靶向该基因，但已经鉴定出许多逆转录病毒插入位点簇，其在T淋巴瘤（Ahi-1、fit-1和Mis-2）以及单核细胞和髓性白血病（Mml 1、Mml 2、Mml 3和Epi-1）中靠近c-myb并且在转录单位之外。先前的分析表明，这些插入对c-myb表达没有一致的影响，这增加了附近其他基因是真正目标的可能性。相比之下，我们的分析建立了四个细胞系从淋巴瘤轴承插入fit-1（fti-1）（猫白血病病毒）和Ahi-1（莫洛尼鼠白血病病毒）显示，这些显示更高的表达水平的c-myb RNA和蛋白质相比，一组表型相似的细胞系缺乏这样的插入。具有长距离c-myb插入的细胞系的一个有趣的特征是，每个细胞系还携带激活的Myc等位基因。Myb和Myc在T细胞淋巴瘤中致癌协同作用的潜力在T细胞隔室中过表达两种基因的等位基因的转基因小鼠中得到证实，进一步证实了c-myb作为长距离激活的主要靶点的情况。相反，c-myb邻近基因（HBS 1和FLJ 20069）的定位和分析表明，这些基因的表达与前病毒插入的存在并不相关。一个可能的解释c-myb的矛盾行为提供了一个小鼠T淋巴瘤系轴承插入在Ahi-1（p/m16 i），可再现下调c-myb RNA和蛋白质的非常低的水平或检测不到的水平，在长期培养。我们的观察暗示c-myb作为逆转录病毒插入上游和下游的关键目标。然而，过度表达可能会在体外生长过程中变得不稳定，也许在体内肿瘤进展过程中，为先前观察到的逆转录病毒插入和c-myb表达水平之间的不一致性提供了潜在的理由。
The c-myb oncogene is a frequent target for retroviral activation in hemopoietic tumors of avian and mammalian species. While insertions can target the gene directly, numerous clusters of retroviral insertion sites have been identified which map close to c-myb and outside the transcription unit in T-lymphomas (Ahi-1, fit-1, and Mis-2) and monocytic and myeloid leukemias (Mml1, Mml2, Mml3, and Epi-1). Previous analyses showed no consistent effect of these insertions on c-myb expression, raising the possibility that other nearby genes were the true targets. In contrast, our analysis of four cell lines established from lymphomas bearing insertions at fit-1 (fti-1) (feline leukemia virus) and Ahi-1 (Moloney murine leukemia virus) shows that these display higher expression levels of c-myb RNA and protein compared to a panel of phenotypically similar cell lines lacking such insertions. An interesting feature of the cell lines with long-range c-myb insertions was that each also carried an activated Myc allele. The potential for oncogenic synergy between Myb and Myc in T-cell lymphoma was confirmed in transgenic mice overexpressing alleles of both genes in the T-cell compartment, lending further credence to the case for c-myb as the major target for long-range activation. In contrast, mapping and analysis of c-myb neighboring genes (HBS1 and FLJ20069) showed that the expression of these genes did not correlate well with the presence of proviral insertions. A possible explanation for the paradoxical behavior of c-myb was provided by one of the murine T-lymphoma lines bearing an insertion at Ahi-1 (p/m16i) that reproducibly down-regulated c-myb RNA and protein to very low levels or undetectable levels on prolonged culture. Our observations implicate c-myb as a key target of upstream and downstream retroviral insertions. However, overexpression may become dispensable during outgrowth in vitro, and perhaps during tumor progression in vivo, providing a potential rationale for the previously observed discordance between retroviral insertion and c-myb expression levels.