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Mammalian target of rapamycin activity is required for expansion of CD34+ hematopoietic progenitor cells

By C.R. Geest, G.J.T. Zwartkruis, E. Vellenga, P.J. Coffer and M. Buitenhuis


Background\ud The mammalian target of rapamycin is a conserved protein kinase known to regulate protein\ud synthesis, cell size and proliferation. Aberrant regulation of mammalian target of\ud rapamycin activity has been observed in hematopoietic malignancies, including acute\ud leukemias and myelodysplastic syndromes, suggesting that correct regulation of mammalian\ud target of rapamycin is critical for normal hematopoiesis.\ud Design and Methods\ud An ex vivo granulocyte differentiation system was utilized to investigate the role of mammalian\ud target of rapamycin in the regulation of myelopoiesis.\ud Results\ud Inhibition of mammalian target of rapamycin activity, with the pharmacological inhibitor\ud rapamycin, dramatically reduced hematopoietic progenitor expansion, without altering\ud levels of apoptosis or maturation. Moreover, analysis of distinct hematopoietic progenitor\ud populations revealed that rapamycin treatment inhibited the expansion potential of committed\ud CD34+ lineage-positive progenitors, but did not affect early hematopoietic progenitors.\ud Further examinations showed that these effects of rapamycin on progenitor expansion\ud might involve differential regulation of protein kinase B and mammalian target of\ud rapamycin signaling.\ud Conclusions\ud Together, these results indicate that mammalian target of rapamycin activity is essential\ud for expansion of CD34+ hematopoietic progenitor cells during myelopoiesis. Modulation\ud of the mammalian target of rapamycin pathway may be of benefit in the design of new\ud therapies to control hematologic malignancie

Topics: Geneeskunde, Geneeskunde, Geneeskunde, mammalian target of rapamycin, mTOR, rapamycin, myeloid, hematopoiesis, CD34+
Year: 2009
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