Lee Pui Y, Sykes David B, Ameri Sarah, Kalaitzidis Demetrios, Charles Julia F, Nelson-Maney Nathan, Wei Kevin, Cunin Pierre, Morris Allyn, Cardona Astrid E, Root David E, Scadden David T, Nigrovic Peter A
Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA.
Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02115, USA.
Sci Immunol. 2017 May 26;2(11). doi: 10.1126/sciimmunol.aam6641.
Monocytes are derived from hematopoietic stem cells through a series of intermediate progenitor stages, but the factors that regulate this process are incompletely defined. Using a Ccr2/Cxcr1 dual-reporter system to model murine monocyte ontogeny, we conducted a small-molecule screen that identified an essential role of mechanistic target of rapamycin complex 1 (mTORC1) in the development of monocytes and other myeloid cells. Confirmatory studies using mice with inducible deletion of the mTORC1 component Raptor demonstrated absence of mature circulating monocytes, as well as disruption in neutrophil and dendritic cell development, reflecting arrest of terminal differentiation at the granulocyte-monocyte progenitor stage. Conversely, excess activation of mTORC1 through deletion of the mTORC1 inhibitor tuberous sclerosis complex 2 promoted spontaneous myeloid cell development and maturation. Inhibitor studies and stage-specific expression profiling identified failure to down-regulate the transcription factor Myc by the mTORC1 target ribosomal S6 kinase 1 (S6K1) as the mechanistic basis for disrupted myelopoiesis. Together, these findings define the mTORC1-S6K1-Myc pathway as a key checkpoint in terminal myeloid development.
单核细胞通过一系列中间祖细胞阶段由造血干细胞衍生而来，但调节这一过程的因素尚未完全明确。我们使用Ccr2/Cxcr1双报告系统对小鼠单核细胞发生进行建模，开展了一项小分子筛选，确定了雷帕霉素复合物1（mTORC1）的机制靶点在单核细胞和其他髓系细胞发育中的关键作用。使用可诱导缺失mTORC1组分Raptor的小鼠进行的验证性研究表明，成熟循环单核细胞缺失，同时中性粒细胞和树突状细胞发育受到破坏，这反映了在粒细胞-单核细胞祖细胞阶段终末分化的停滞。相反，通过缺失mTORC1抑制剂结节性硬化复合物2来过度激活mTORC1，可促进髓系细胞的自发发育和成熟。抑制剂研究和阶段特异性表达谱分析确定，mTORC1靶点核糖体S6激酶1（S6K1）未能下调转录因子Myc是骨髓生成受破坏的机制基础。这些发现共同确定了mTORC1-S6K1-Myc通路是终末髓系发育中的一个关键检查点。
