Department of Clinical and Biological Sciences, University of Turin, 10043 Turin, Italy.
Department of Neuroscience Rita Levi Montalcini, Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043 Turin, Italy.
Int J Mol Sci. 2023 Jan 8;24(2):1234. doi: 10.3390/ijms24021234.
Hypoxia is a critical condition that governs survival, self-renewal, quiescence, metabolic shift and refractoriness to leukemic stem cell (LSC) therapy. The present study aims to investigate the hypoxia-driven regulation of the mammalian Target of the Rapamycin-2 (mTORC2) complex to unravel it as a novel potential target in chronic myeloid leukemia (CML) therapeutic strategies. After inducing hypoxia in a CML cell line model, we investigated the activities of mTORC1 and mTORC2. Surprisingly, we detected a significant activation of mTORC2 at the expense of mTORC1, accompanied by the nuclear localization of the main substrate phospho-Akt (Ser473). Moreover, the Gene Ontology analysis of CML patients' CD34+ cells showed enrichment in the mTORC2 signature, further strengthening our data. The deregulation of mTOR complexes highlights how hypoxia could be crucial in CML development. In conclusion, we propose a mechanism by which CML cells residing under a low-oxygen tension, i.e., in the leukemia quiescent LSCs, singularly regulate the mTORC2 and its downstream effectors.
缺氧是一种关键的状态，它控制着生存、自我更新、静止、代谢转变以及白血病干细胞（LSC）治疗的抵抗。本研究旨在探究缺氧对哺乳动物雷帕霉素靶蛋白复合物 2（mTORC2）的调控作用，以揭示其作为慢性髓系白血病（CML）治疗策略中的一个新的潜在靶点。在 CML 细胞系模型中诱导缺氧后，我们研究了 mTORC1 和 mTORC2 的活性。令人惊讶的是，我们检测到 mTORC2 的显著激活，而 mTORC1 的活性则受到抑制，同时主要底物磷酸化 Akt（Ser473）发生核定位。此外，CML 患者 CD34+细胞的基因本体分析显示 mTORC2 特征明显富集，进一步证实了我们的数据。mTOR 复合物的失调突显了缺氧在 CML 发展中的重要性。总之，我们提出了一种机制，即低氧环境下（即在白血病静止的 LSCs 中）的 CML 细胞可以单独调节 mTORC2 及其下游效应物。
