Department of Biotechnology, Jinan University, Guangzhou, Guangdong, China.
Haematologica. 2013 Sep;98(9):1353-8. doi: 10.3324/haematol.2012.080424. Epub 2013 May 28.
mTOR integrates signals from nutrients and growth factors to control protein synthesis, cell growth, and survival. Although mTOR has been established as a therapeutic target in hematologic malignancies, its physiological role in regulating hematopoiesis remains unclear. Here we show that conditional gene targeting of mTOR causes bone marrow failure and defects in multi-lineage hematopoiesis including myelopoiesis, erythropoiesis, thrombopoiesis, and lymphopoiesis. mTOR deficiency results in loss of quiescence of hematopoietic stem cells, leading to a transient increase but long-term exhaustion and defective engraftment of hematopoietic stem cells in lethally irradiated recipient mice. Furthermore, ablation of mTOR causes increased apoptosis in lineage-committed blood cells but not hematopoietic stem cells, indicating a differentiation stage-specific function. These results demonstrate that mTOR is essential for hematopoietic stem cell engraftment and multi-lineage hematopoiesis.
mTOR 整合了来自营养物质和生长因子的信号，以控制蛋白质合成、细胞生长和存活。虽然 mTOR 已被确立为血液恶性肿瘤的治疗靶点，但它在调节造血方面的生理作用仍不清楚。在这里，我们表明 mTOR 的条件性基因靶向导致骨髓衰竭和多谱系造血缺陷，包括髓系造血、红细胞生成、血小板生成和淋巴造血。mTOR 缺乏导致造血干细胞的静止丧失，导致在致死性照射的受体小鼠中，造血干细胞短暂增加但长期耗尽和植入缺陷。此外，mTOR 的缺失导致谱系定向血细胞的凋亡增加，但造血干细胞没有，表明其具有分化阶段特异性的功能。这些结果表明 mTOR 对于造血干细胞植入和多谱系造血是必需的。
