TY  - JOUR
A1  - Klein-Hessling, Stefan
A1  - Rudolf, Ronald
A1  - Muhammad, Khalid
A1  - Knobeloch, Klaus-Peter
A1  - Maqbool, Muhammad Ahmad
A1  - Cauchy, Pierre
A1  - Andrau, Jean-Christophe
A1  - Avots, Andris
A1  - Talora, Claudio
A1  - Ellenrieder, Volker
A1  - Screpanti, Isabella
A1  - Serfling, Edgar
A1  - Patra, Amiya Kumar
T1  - A threshold level of NFATc1 activity facilitates thymocyte differentiation and opposes notch-driven leukaemia development
JF  - Nature Communications
N2  - 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.
KW  - acute lymphocytic leukaemia
KW  - transcription factors
KW  - lymphocyte differentiation
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172974
VL  - 7
ER  -