Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
Proc Natl Acad Sci U S A. 2014 Mar 11;111(10):3805-10. doi: 10.1073/pnas.1320265111. Epub 2014 Feb 24.
mTOR is an evolutionarily conserved kinase that plays a critical role in sensing and responding to environmental determinants. Recent studies have shown that fine-tuning of the activity of mTOR complexes contributes to organogenesis and tumorigenesis. Although rapamycin, an allosteric mTOR inhibitor, is an effective immunosuppressant, the precise roles of mTOR complexes in early T-cell development remain unclear. Here we show that mTORC1 plays a critical role in the development of both early T-cell progenitors and leukemia. Deletion of Raptor, an essential component of mTORC1, produced defects in the earliest development of T-cell progenitors in vivo and in vitro. Deficiency of Raptor resulted in cell cycle abnormalities in early T-cell progenitors that were associated with instability of the Cyclin D2/D3-CDK6 complexes; deficiency of Rictor, an mTORC2 component, did not have the same effect, indicating that mTORC1 and -2 control T-cell development in different ways. In a model of myeloproliferative neoplasm and T-cell acute lymphoblastic leukemia (T-ALL) evoked by Kras activation, Raptor deficiency dramatically inhibited the cell cycle in oncogenic Kras-expressing T-cell progenitors, but not myeloid progenitors, and specifically prevented the development of T-ALL. Although rapamycin treatment significantly prolonged the survival of recipient mice bearing T-ALL cells, rapamycin-insensitive leukemia cells continued to propagate in vivo. In contrast, Raptor deficiency in the T-ALL model resulted in cell cycle arrest and efficient eradication of leukemia. Thus, understanding the cell-context-dependent role of mTORC1 illustrates the potential importance of mTOR signals as therapeutic targets.
mTOR 是一种进化上保守的激酶，在感知和响应环境决定因素方面起着关键作用。最近的研究表明，mTOR 复合物活性的精细调节有助于器官发生和肿瘤发生。虽然雷帕霉素（一种别构 mTOR 抑制剂）是一种有效的免疫抑制剂，但 mTOR 复合物在早期 T 细胞发育中的确切作用仍不清楚。在这里，我们表明 mTORC1 在早期 T 细胞前体和白血病的发育中起着关键作用。Raptor（mTORC1 的必需成分）的缺失导致体内和体外 T 细胞前体的最早发育缺陷。Raptor 的缺乏导致早期 T 细胞前体细胞的细胞周期异常，与细胞周期蛋白 D2/D3-CDK6 复合物的不稳定性有关；mTORC2 成分 Rictor 的缺乏没有相同的效果，表明 mTORC1 和 -2 以不同的方式控制 T 细胞发育。在由 Kras 激活引发的骨髓增生性肿瘤和 T 细胞急性淋巴细胞白血病（T-ALL）模型中，Raptor 的缺失显著抑制了致癌 Kras 表达的 T 细胞前体中的细胞周期，但对髓样前体没有相同的作用，并且专门阻止了 T-ALL 的发展。虽然雷帕霉素治疗显著延长了携带 T-ALL 细胞的受体小鼠的存活时间，但雷帕霉素不敏感的白血病细胞继续在体内繁殖。相比之下，T-ALL 模型中 Raptor 的缺失导致细胞周期停滞并有效地消除了白血病。因此，了解 mTORC1 的细胞上下文依赖性作用说明了 mTOR 信号作为治疗靶点的潜在重要性。
