Runx2 and MYC collaborate in lymphoma development by suppressing apoptotic and growth arrest pathways in vivo
Runx2 and MYC collaborate in lymphoma development by suppressing apoptotic and growth arrest pathways in vivo
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DOI：
10.1158/0008-5472.can-05-3558
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发表时间：
2006-02-15
期刊：
影响因子：
11.2
通讯作者：
Cameron, ER
中科院分区：
文献类型：
--
作者：
Blyth, K;Vaillant, F;Cameron, ER
Ranx和MYC家族的成员被认为是协同致癌基因。在Runx 2/MYC小鼠的这项研究中阐明了这种有效合作的机制。如前所述，Runx 2在胸腺中的异位表达导致肿瘤前状态，其定义为具有不成熟表型和低增殖率的细胞积聚。我们现在表明，c-MYC过表达足以挽救增殖和释放Runx 2施加的分化阻滞。Runx 2表达淋巴瘤的分析揭示了一致的低凋亡率，与MYC小鼠的淋巴瘤相反，MYC小鼠的淋巴瘤通常是高度凋亡的。低凋亡表型在Runx 2/MYC肿瘤中占主导地位，表明Runx 2赋予表达MYC的肿瘤细胞有效的生存优势。在p53杂合子背景下探索了p53通路在Runx 2/MYC肿瘤中的作用。令人惊讶的是，即使在移植后，功能性p53仍保留在体内，而移植的肿瘤细胞在体外显示出快速的等位基因丢失。我们的研究结果表明，Runx 2和MYC克服了不同的“故障安全”的反应，他们的选择是由于他们的能力，以抵消对方的负增长效应的合作基因。此外，Runx 2/MYC组合克服了体内p53途径遗传失活的要求。
Members of the Ranx and MYC families have been implicated as collaborating oncogenes. The mechanism of this potent collaboration is elucidated in this study of Runx2/MYC mice. As shown previously, ectopic expression of Runx2 in the thymus leads to a preneoplastic state defined by an accumulation of cells with an immature phenotype and a low proliferative rate. We now show that c-MYC overexpression is sufficient to rescue proliferation and to release the differentiation block imposed by Runx2. Analysis of Runx2-expressing lymphomas reveals a consistently low rate of apoptosis, in contrast to lymphomas of MYC mice which are often highly apoptotic. The low apoptosis phenotype is dominant in Runx2/MYC tumors, indicating that Runx2 confers a potent survival advantage to MYC-expressing tumor cells. The role of the p53 pathway in Runx2/MYC tumors was explored on a p53 heterozygote background. Surprisingly, functional p53 was retained in vivo, even after transplantation, whereas explanted tumor cells displayed rapid allele loss in vitro. Our results show that Runx2 and MYC overcome distinct "fail-safe" responses and that their selection as collaborating genes is due to their ability to neutralize each other's negative growth effect. Furthermore, the Runx2/MYC combination overcomes the requirement for genetic inactivation of the p53 pathway in vivo.