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

Christian R. Geest, Fried J. Zwartkruis, Edo Vellenga, Paul J. Coffer, Miranda Buitenhuis*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    18 Citations (Scopus)

    Abstract

    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 malignancies.

    Original languageEnglish
    Pages (from-to)901-910
    Number of pages10
    JournalHaematologica
    Volume94
    Issue number7
    DOIs
    Publication statusPublished - Jul-2009

    Keywords

    • mammalian target of rapamycin
    • mTOR
    • rapamycin
    • myeloid
    • hematopoiesis
    • CD34(+)
    • ACUTE MYELOID-LEUKEMIA
    • PROTEIN-KINASE-B
    • TRANSLATION INITIATION
    • MEGAKARYOCYTE PROGENITORS
    • CYCLE PROGRESSION
    • GROWTH CONTROL
    • IN-VITRO
    • T-CELLS
    • MTOR
    • DIFFERENTIATION

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