Division of Oncology, Department of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Proc Natl Acad Sci U S A. 2011 Oct 18;108(42):17432-7. doi: 10.1073/pnas.1107303108. Epub 2011 Oct 3.
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 Eμ-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.
抑制致癌水平的 MYC 足以诱导持续的肿瘤消退，与增殖停滞、分化、细胞衰老和/或细胞凋亡相关，这种现象被称为癌基因成瘾。然而，在条件性转基因小鼠模型中，Eμ-tTA/tetO-MYC T 细胞急性淋巴细胞白血病中 MYC 的长期失活后，一些肿瘤会复发，这与靶向治疗后经常在人类肿瘤中观察到的情况类似。在这里，我们报告说，这些复发性淋巴瘤表达转基因或内源性 Myc，尽管在许多情况下，其水平低于原始肿瘤中的水平，这表明肿瘤仍然对 MYC 有依赖性。许多复发性淋巴瘤（76%）携带四环素转录激活剂的突变，导致即使存在强力霉素，MYC 转基因也会表达。一些剩余的复发性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，我们证实了原发性和复发性肿瘤具有高度相似的转录组。重要的是，shRNA 介导的对复发性肿瘤中高水平 MYC 的抑制既抑制了增殖，又增加了细胞凋亡，证实这些肿瘤仍然对癌基因有依赖性。这些结果表明，由 MYC 诱导的肿瘤仍然依赖于这种致癌基因的过度表达。
