Cell competition is a tumour suppressor mechanism in the thymus
Cell competition is a tumour suppressor mechanism in the thymus
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DOI：
10.1038/nature13317
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发表时间：
2014-05-22
期刊：
影响因子：
64.8
通讯作者：
Rodewald, Hans-Reimer
中科院分区：
文献类型：
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作者：
Martins, Vera C.;Busch, Katrin;Rodewald, Hans-Reimer
细胞竞争是一个新兴的原则，在发展和疾病的细胞健康的选择。竞争可能与癌症有关，但竞争缺陷与肿瘤发生之间的实验联系是难以捉摸的。在胸腺中，T淋巴细胞由前体细胞发育而成，这些前体细胞不断被骨髓来源的祖细胞取代。在这里，我们表明，在小鼠中，这种营业额是由“年轻的”骨髓来源和“老”胸腺居民祖细胞之间的自然细胞竞争，虽然遗传相同，执行差异基因表达程序。细胞竞争的破坏导致祖细胞自我更新、Hmga 1上调、转化和T细胞急性淋巴细胞白血病（T-ALL），其在病理学、基因组病变、白血病相关转录物和Notch 1中的激活突变方面类似于人类疾病。因此，细胞竞争是胸腺中的肿瘤抑制机制。未能通过细胞竞争选择合适的祖细胞可能解释X连锁严重联合免疫缺陷患者的白血病，这些患者在用基因校正的自体祖细胞治疗后显示胸腺自主T细胞发育。
Cell competitionis an emerging principle underlying selection for cellular fitness during development and disease. Competition may be relevant for cancer, but an experimental link between defects in competition and tumorigenesis is elusive. In the thymus, T lymphocytes develop from precursors that are constantly replaced by bone-marrow-derived progenitors. Here we show that in mice this turnover is regulated by natural cell competition between 'young' bone-marrow-derived and 'old' thymus-resident progenitors that, although genetically identical, execute differential gene expression programs. Disruption of cell competition leads to progenitor self-renewal, upregulation of Hmga1, transformation, and T-cell acute lymphoblastic leukaemia (T-ALL) resembling the human disease in pathology, genomic lesions, leukaemia-associated transcripts, and activating mutations in Notch1. Hence, cell competition is a tumour suppressor mechanism in the thymus. Failure to select fit progenitors through cell competition may explain leukaemia in X-linked severe combined immune deficiency patients who showed thymus-autonomous T-cell development after therapy with gene-corrected autologous progenitors.