Geest Christian R, Zwartkruis Fried J, Vellenga Edo, Coffer Paul J, Buitenhuis Miranda
Department of Immunology, Molecular Immunology Lab, UMC, Utrecht, The Netherlands.
Haematologica. 2009 Jul;94(7):901-10. doi: 10.3324/haematol.13766. Epub 2009 Jun 16.
The mammalian target of rapamycin is a conserved protein kinase known to regulate protein synthesis, cell size and proliferation. Aberrant regulation of mammalian target of rapamycin activity has been observed in hematopoietic malignancies, including acute leukemias and myelodysplastic syndromes, suggesting that correct regulation of mammalian target of rapamycin is critical for normal hematopoiesis.
An ex vivo granulocyte differentiation system was utilized to investigate the role of mammalian target of rapamycin in the regulation of myelopoiesis.
Inhibition of mammalian target of rapamycin activity, with the pharmacological inhibitor rapamycin, dramatically reduced hematopoietic progenitor expansion, without altering levels of apoptosis or maturation. Moreover, analysis of distinct hematopoietic progenitor populations revealed that rapamycin treatment inhibited the expansion potential of committed CD34(+) lineage-positive progenitors, but did not affect early hematopoietic progenitors. Further examinations showed that these effects of rapamycin on progenitor expansion might involve differential regulation of protein kinase B and mammalian target of rapamycin signaling.
Together, these results indicate that mammalian target of rapamycin activity is essential for expansion of CD34(+) hematopoietic progenitor cells during myelopoiesis. Modulation of the mammalian target of rapamycin pathway may be of benefit in the design of new therapies to control hematologic malignancies.
雷帕霉素的哺乳动物靶点是一种保守的蛋白激酶，已知其可调节蛋白质合成、细胞大小和增殖。在包括急性白血病和骨髓增生异常综合征在内的血液系统恶性肿瘤中，已观察到雷帕霉素哺乳动物靶点活性的异常调节，这表明雷帕霉素哺乳动物靶点的正确调节对正常造血至关重要。
利用体外粒细胞分化系统研究雷帕霉素哺乳动物靶点在骨髓生成调节中的作用。
使用药理抑制剂雷帕霉素抑制雷帕霉素哺乳动物靶点活性，可显著减少造血祖细胞的扩增，而不改变细胞凋亡或成熟水平。此外，对不同造血祖细胞群体的分析表明，雷帕霉素处理可抑制定向CD34(+)谱系阳性祖细胞的扩增潜能，但不影响早期造血祖细胞。进一步研究表明，雷帕霉素对祖细胞扩增的这些作用可能涉及蛋白激酶B和雷帕霉素哺乳动物靶点信号通路的差异调节。
总之，这些结果表明雷帕霉素哺乳动物靶点活性在骨髓生成过程中对CD34(+)造血祖细胞的扩增至关重要。调节雷帕霉素哺乳动物靶点通路可能有助于设计控制血液系统恶性肿瘤的新疗法。
