Calcium and Calcineurin-NFAT Signaling Regulate Granulocyte-Monocyte Progenitor Cell Cycle via Flt3-L

Authors

  • Jan Fric,

    Corresponding author
    1. Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore
    • Correspondence: Prof. Paola Ricciardi-Castagnoli, Ph.D., Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore. Telephone: 65-6407-0002; Fax: 65-6464-2057; e-mail: paola_castagnoli@immunol.a-star.edu.sg; or Jan Fric, Ph.D., Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #04-06 Immunos, Biopolis, Singapore 138648. Telephone: 65-6407-0068; Fax: 65-6464-2057; e-mail: jan_fric@immunol.a-star.edu.sg

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  • Clarice X.F. Lim,

    1. Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore
    2. Institute of Pathophysiology and Immunology, Medical University Graz, Austria
    3. Department of Medicine I, Institute for Cancer Research, Medical University of Vienna, Austria
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  • Alexandra Mertes,

    1. Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore
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  • Bernett T.K. Lee,

    1. Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore
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  • Elena Viganò,

    1. Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore
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  • Jinmiao Chen,

    1. Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore
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  • Francesca Zolezzi,

    1. Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore
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  • Michael Poidinger,

    1. Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore
    2. Department of Biological Sciences, National University of Singapore, Singapore
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  • Anis Larbi,

    1. Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore
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  • Herbert Strobl,

    1. Institute of Pathophysiology and Immunology, Medical University Graz, Austria
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  • Teresa Zelante,

    1. Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore
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  • Paola Ricciardi-Castagnoli

    Corresponding author
    1. Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore
    • Correspondence: Prof. Paola Ricciardi-Castagnoli, Ph.D., Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore. Telephone: 65-6407-0002; Fax: 65-6464-2057; e-mail: paola_castagnoli@immunol.a-star.edu.sg; or Jan Fric, Ph.D., Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #04-06 Immunos, Biopolis, Singapore 138648. Telephone: 65-6407-0068; Fax: 65-6464-2057; e-mail: jan_fric@immunol.a-star.edu.sg

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Abstract

Maintenance of myeloid progenitor cells is controlled by complex regulatory mechanisms and is orchestrated by multiple different transcription factors. Here, we report that the activation of the transcription factor nuclear factor of activated T cells (NFAT) by calcium-sensing protein calcineurin inhibits the proliferation of myeloid granulocyte–monocyte progenitors (GMPs). Myeloid progenitor subtypes exhibit variable sensitivity to induced Ca2+ entry and consequently display differential engagement of the calcineurin-NFAT pathway. This study shows that inhibition of the calcineurin-NFAT pathway enhances the proliferation of GMPs both in vitro and in vivo and demonstrates that calcineurin-NFAT signaling in GMPs is initiated by Flt3-L. Inhibition of the calcineurin-NFAT pathway modified expression of the cell cycle regulation genes Cdk4, Cdk6, and Cdkn1a (p21), thus enabling rapid cell cycle progression specifically in GMPs. NFAT inhibitor drugs are extensively used in the clinic to restrict the pathological activation of lymphoid cells, and our data reveal for the first time that these therapies also exert potent effects on maintenance of the myeloid cell compartment through specific regulation of GMP proliferation. Stem Cells 2014;32:3232–3244

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