Lymphomas that recur after MYC suppression continue to exhibit oncogene addiction
Lymphomas that recur after MYC suppression continue to exhibit oncogene addiction
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DOI：
10.1073/pnas.1107303108
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发表时间：
2011-10-18
影响因子：
11.1
通讯作者：
Felsher, Dean W.
中科院分区：
文献类型：
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作者：
Choi, Peter S.;van Riggelen, Jan;Felsher, Dean W.
抑制MYC的致癌水平足以诱导与增殖停滞、分化、细胞衰老和/或凋亡相关的持续的肿瘤消退，这一现象被称为癌基因成瘾。然而，在条件转基因小鼠模型中的MYC长期失活后，一些肿瘤复发，重现了在靶向治疗下在人类肿瘤中经常观察到的情况。在这里，我们报告这些复发的淋巴瘤表达转基因或内源性Myc，尽管在许多情况下低于原始肿瘤的水平，这表明肿瘤继续对MYC上瘾。许多复发的淋巴瘤(76%)含有四环素反式激活因子的突变，导致即使在多西环素存在的情况下也能表达MYC转基因。一些残留的复发肿瘤表达高水平的内源性Myc，这与内源性Myc基因座的基因组重排或Notch1的激活有关。通过基因表达谱分析，我们证实了原发和复发肿瘤具有高度相似的转录本。重要的是，shRNA介导的抑制复发肿瘤中高水平的MYC既引起了增殖抑制，又增加了细胞凋亡，证实了这些肿瘤仍然对癌基因上瘾。这些结果表明，MYC诱导的肿瘤仍然对该癌基因的过度表达上瘾。
The suppression of oncogenic levels of MYC is sufficient to induce sustained tumor regression associated with proliferative arrest, differentiation, cellular senescence, and/or apoptosis, a phenomenon known as oncogene addiction. However, after prolonged inactivation of MYC in a conditional transgenic mouse model of E mu-tTA/tetO-MYC T-cell acute lymphoblastic leukemia, some of the tumors recur, recapitulating what is frequently observed in human tumors in response to targeted therapies. Here we report that these recurring lymphomas express either transgenic or endogenous Myc, albeit in many cases at levels below those in the original tumor, suggesting that tumors continue to be addicted to MYC. Many of the recurring lymphomas (76%) harbored mutations in the tetracycline transactivator, resulting in expression of the MYC transgene even in the presence of doxycycline. Some of the remaining recurring tumors expressed high levels of endogenous Myc, which was associated with a genomic rearrangement of the endogenous Myc locus or activation of Notch1. By gene expression profiling, we confirmed that the primary and recurring tumors have highly similar transcriptomes. Importantly, shRNA-mediated suppression of the high levels of MYC in recurring tumors elicited both suppression of proliferation and increased apoptosis, confirming that these tumors remain oncogene addicted. These results suggest that tumors induced by MYC remain addicted to overexpression of this oncogene.