S6K1 regulates hematopoietic stem cell self-renewal and leukemia maintenance
S6K1 regulates hematopoietic stem cell self-renewal and leukemia maintenance
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DOI：
10.1172/jci84565
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发表时间：
2016-07-01
影响因子：
15.9
通讯作者：
Kapur, Reuben
中科院分区：
文献类型：
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作者：
Ghosh, Joydeep;Kobayashi, Michihiro;Kapur, Reuben
mTOR通路的过度活化损害造血干细胞（HSC）功能并促进白血病发生。mTORC 1和mTORC 2差异控制正常和白血病干细胞功能。mTORC 1调节p70核糖体蛋白56激酶1（5617）和真核起始因子4 E结合（eIF 4 E结合）蛋白1（4 E-BP 1），mTORC 2调节AKT活化。考虑到mTORC 1和mTORC 2信号通路之间发生的广泛串扰，我们评估了mTORC 1底物561 β 1在正常HSC功能调节和混合谱系白血病（MLL）融合癌基因MLL-AF 9驱动的白血病发生中的作用。我们证明561 β 1缺陷通过减少p21表达而损害鼠HSC的自我更新。561 β 1的缺失也通过调节AKT和4 E-BP 1磷酸化而改善了移植MLL-AF 9阳性白血病干细胞的小鼠的存活率。综上所述，这些结果表明5610通过mTOR途径的多个靶点起作用，以促进自我更新和白血病进展。鉴于最近对S6 K1作为癌症潜在治疗靶点的兴趣，我们的结果进一步支持靶向该分子作为治疗骨髓恶性肿瘤的潜在策略。
Hyperactivation of the mTOR pathway impairs hematopoietic stem cell (HSC) functions and promotes leukemogenesis. mTORC1 and mTORC2 differentially control normal and leukemic stem cell functions. mTORC1 regulates p70 ribosomal protein 56 kinase 1(5617) and eukaryotic initiation factor 4E-binding (eIF4E-binding) protein 1 (4E-BP1), and mTORC2 modulates AKT activation. Given the extensive crosstalk that occurs between mTORC1 and mTORC2 signaling pathways, we assessed the role of the mTORC1 substrate 561(1 in the regulation of both normal HSC functions and in leukemogenesis driven by the mixed lineage leukemia (MLL) fusion oncogene MLL-AF9. We demonstrated that 561(1 deficiency impairs self-renewal of murine HSCs by reducing p21 expression. Loss of 561(1 also improved survival in mice transplanted with MLL-AF9-positive leukemic stem cells by modulating AKT and 4E-BP1 phosphorylation. Taken together, these results suggest that 5610 acts through multiple targets of the mTOR pathway to promote self-renewal and leukemia progression. Given the recent interest in S6K1 as a potential therapeutic target in cancer, our results further support targeting this molecule as a potential strategy for treatment of myeloid malignancies.