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A threshold level of NFATc1 activity facilitates thymocyte differentiation and opposes notch-driven leukaemia development

Author

Listed:
  • Stefan Klein-Hessling

    (Institute for Pathology, University of Wuerzburg)

  • Ronald Rudolf

    (Institute for Pathology, University of Wuerzburg)

  • Khalid Muhammad

    (Institute for Pathology, University of Wuerzburg)

  • Klaus-Peter Knobeloch

    (Institute of Neuropathology, University Clinic Freiburg)

  • Muhammad Ahmad Maqbool

    (Institute de Génétique Moléculaire de Montpellier (IGMM))

  • Pierre Cauchy

    (Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham)

  • Jean-Christophe Andrau

    (Institute de Génétique Moléculaire de Montpellier (IGMM))

  • Andris Avots

    (Institute for Pathology, University of Wuerzburg)

  • Claudio Talora

    (Laboratory of Molecular Pathology, Sapienza University of Rome)

  • Volker Ellenrieder

    (University of Goettingen)

  • Isabella Screpanti

    (Laboratory of Molecular Pathology, Sapienza University of Rome)

  • Edgar Serfling

    (Institute for Pathology, University of Wuerzburg)

  • Amiya Kumar Patra

    (Institute for Pathology, University of Wuerzburg
    Present address: Institute of Translational and Stratified Medicine Peninsula Schools of Medicine and Dentistry, University of Plymouth, Plymouth Science Park, Research Way, Plymouth PL6 8BU, UK.)

Abstract

NFATc1 plays a critical role in double-negative thymocyte survival and differentiation. However, the signals that regulate Nfatc1 expression are incompletely characterized. Here we show a developmental stage-specific differential expression pattern of Nfatc1 driven by the distal (P1) or proximal (P2) promoters in thymocytes. Whereas, preTCR-negative thymocytes exhibit only P2 promoter-derived Nfatc1β expression, preTCR-positive thymocytes express both Nfatc1β and P1 promoter-derived Nfatc1α transcripts. Inducing NFATc1α activity from P1 promoter in preTCR-negative thymocytes, in addition to the NFATc1β from P2 promoter impairs thymocyte development resulting in severe T-cell lymphopenia. In addition, we show that NFATc1 activity suppresses the B-lineage potential of immature thymocytes, and consolidates their differentiation to T cells. Further, in the pTCR-positive DN3 cells, a threshold level of NFATc1 activity is vital in facilitating T-cell differentiation and to prevent Notch3-induced T-acute lymphoblastic leukaemia. Altogether, our results show NFATc1 activity is crucial in determining the T-cell fate of thymocytes.

Suggested Citation

  • Stefan Klein-Hessling & Ronald Rudolf & Khalid Muhammad & Klaus-Peter Knobeloch & Muhammad Ahmad Maqbool & Pierre Cauchy & Jean-Christophe Andrau & Andris Avots & Claudio Talora & Volker Ellenrieder &, 2016. "A threshold level of NFATc1 activity facilitates thymocyte differentiation and opposes notch-driven leukaemia development," Nature Communications, Nature, vol. 7(1), pages 1-14, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11841
    DOI: 10.1038/ncomms11841
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