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Published online before print August 3, 2004

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(Journal of Leukocyte Biology. 2004;76:1057-1065.)
© 2004 by Society for Leukocyte Biology

Expression and regulation of NFAT (nuclear factors of activated T cells) in human CD34⁺ cells: down-regulation upon myeloid differentiation

Alexander Kiani^*,1, Ivonne Habermann^*, Michael Haase, Silvia Feldmann^*, Sabine Boxberger^*, Maria A. Sanchez-Fernandez^*,2, Christian Thiede^*, Martin Bornhäuser^* and Gerhard Ehninger^*

^* Department of Medicine I and
Institute of Pathology, University Hospital Carl Gustav Carus at the University of Dresden Technical Center, Germany

¹ Correspondence: Medizinische Klinik und Poliklinik I an der Technischen Universität Dresden, Fetscherstr. 48, 01307 Dresden, Germany. E-mail: alexander.kiani{at}uniklinikum-dresden.de

The calcineurin-dependent, cyclosporin A (CsA)-sensitive transcription factor nuclear factor of activated T cells (NFAT) represents a group of proteins, which is well-characterized as a central regulatory element of cytokine expression in activated T cells. In contrast, little is known about the expression or function of NFAT family members in myeloid cells; moreover, it is unclear whether they are expressed by hematopoietic stem/progenitor cells. Here, we show that NFATc2 (NFAT1) is expressed at high levels in CD34⁺ cells and megakaryocytes but not in cells committed to the neutrophilic, monocytic, or erythroid lineages. Cytokine-induced in vitro differentiation of CD34⁺ cells into neutrophil granulocytes results in the rapid suppression of NFATc2 RNA and protein. NFATc2 dephosphorylation/rephosphorylation as well as nuclear/cytoplasmic translocation in CD34⁺ cells follow the same calcineurin-dependent pattern as in T lymphocytes, suggesting that NFATc2 activation in these cells is equally sensitive to inhibition with CsA. Finally, in vitro proliferation, but not differentiation, of CD34⁺ cells cultured in the presence of fms-like tyrosine kinase 3 ligand (FLT3L), stem cell factor, granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin-3, and G-CSF is profoundly inhibited by treatment with CsA in a dose-dependent manner. These results suggest a novel and unexpected role for members of the NFAT transcription factor family in the hematopoietic system.

Key Words: cyclosporin A • bone marrow • neutrophil granulocytes • megakaryocytes • proliferation

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