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


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 malignancies.
Geest
Christian R
CR
Department of Immunology, Molecular Immunology Lab, UMC, Utrecht, The Netherlands.
Zwartkruis
Fried J
FJ
Vellenga
Edo
E
Coffer
Paul J
PJ
Buitenhuis
Miranda
M
D018952:Antigens, CD34 / Q000096:biosynthesis*; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D005312:Fetal Blood / Q000166:cytology; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation; D006098:Granulocytes / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D038042:Myelopoiesis; D011494:Protein Kinases / Q000096:biosynthesis*; D012107:Research Design; D013234:Stem Cells / Q000166:cytology; D058570:TOR Serine-Threonine Kinases
D018952:Antigens, CD34; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases