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

Stefan Klein-Hessling, Ronald Rudolf, Khalid Muhammad, Klaus-Peter Knobeloch, Muhammad Ahmad Maqbool, Pierre Cauchy, Jean-Christophe Andrau, Andris Avots, Claudio Talora, Volker Ellenrieder, Isabella Screpanti, Edgar Serfling and Amiya Kumar Patra ()
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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

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11841

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