Background
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.
Design and Methods
An ex vivo granulocyte differentiation system was utilized to investigate the role of mammalian
target of rapamycin in the regulation of myelopoiesis.
Results
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.
Conclusions
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 malignancie
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