Chromosomal location targets different MYC family gene members for oncogenic translocations
Chromosomal location targets different MYC family gene members for oncogenic translocations
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DOI：
10.1073/pnas.0812763106
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发表时间：
2009-02-17
影响因子：
11.1
通讯作者：
Alt, Frederick W.
中科院分区：
文献类型：
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作者：
Gostissa, Monica;Ranganath, Sheila;Alt, Frederick W.
MYC家族的细胞癌基因包括c-Myc、N-myc和L-myc，它们编码参与控制细胞增殖和死亡的转录调节因子。因此，这些基因被异常激活，并在特定类型的癌症中表达。例如，c-Myc易位在人类B淋巴样肿瘤中频繁发生，而N-myc基因扩增在人类神经母细胞瘤中频繁发生。观察到的异常，特别是MYC家族基因和特定的恶性肿瘤亚组之间的关联可能至少部分地反映了给定的MYC基因在表达或功能上的组织特异性差异。由于c-Myc和N-myc共享大量的功能冗余，另一个可能影响肿瘤特异性基因激活的因素将是针对特定肿瘤前体细胞类型中给定MYC基因的异常(例如，易位)的机制。我们先前已经证明，缺乏DNA Ligase4(Lig4)非同源DNA末端连接因子和p53肿瘤抑制基因的小鼠通常会患上祖细胞(PRO)-B细胞淋巴瘤，这种淋巴瘤含有导致c-Myc扩增的易位。在此，我们报告了一种c-Myc编码序列被N-myc编码序列取代的修饰等位基因(NCR等位基因)，它与野生型c-Myc等位基因在Lig4/P53缺陷的前B细胞淋巴瘤模型中作为致癌易位和扩增的目标竞争很好。在携带野生型c-Myc基因或NCR等位基因的肿瘤中，肿瘤的发病、类型和细胞学异常相似。我们的结果支持这样的观点，即与内源性N-myc基因相比，c-Myc基因座的特殊特征选择了它作为Lig4/P53缺陷的Pro-B细胞淋巴瘤的优先易位/扩增靶点。
The MYC family of cellular oncogenes includes c-Myc, N-myc, and L-myc, which encode transcriptional regulators involved in the control of cell proliferation and death. Accordingly, these genes become aberrantly activated and expressed in specific types of cancers. For example, c-Myc translocations occur frequently in human B lymphoid tumors, while N-myc gene amplification is frequent in human neuroblastomas. The observed association between aberrations in particular MYC family genes and specific subsets of malignancies might reflect, at least in part, tissue-specific differences in expression or function of a given MYC gene. Since c-Myc and N-myc share substantial functional redundancy, another factor that could influence tumor-specific gene activation would be mechanisms that target aberrations ( e. g., translocations) in a given MYC gene in a particular tumor progenitor cell type. We have previously shown that mice deficient for the DNA Ligase4 (Lig4) nonhomologous DNA end-joining factor and the p53 tumor suppressor routinely develop progenitor (pro)-B cell lymphomas that harbor translocations leading to c-Myc amplification. Here, we report that a modified allele in which the c-Myc coding sequence is replaced by N-myc coding sequence (NCR allele) competes well with the wild-type c-Myc allele as a target for oncogenic translocations and amplifications in the Lig4/p53-deficient pro-B cell lymphoma model. Tumor onset, type, and cytological aberrations are similar in tumors harboring either the wild-type c-Myc gene or the NCR allele. Our results support the notion that particular features of the c-Myc locus select it as a preferential translocation/amplification target, compared to the endogenous N-myc locus, in Lig4/p53-deficient pro-B cell lymphomas.