A threshold level of NFATc1 activity is critical for thymocyte differentiation and to prevent leukemia development

NFATc1 plays a critical role in double-negative thymocyte survival and differentiation. However, the signals that regulate Nfatc1 expression are unknown. 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 exhibited only P2 promoter-derived Nfatc1b expression, preTCR-positive thymocytes expressed both Nfatc1b and P1 promoter-derived Nfatc1a transcripts. Inducing NFATc1a activity from P1 promoter in preTCR-negative thymocytes, in addition to the NFATc1a from P2 promoter impaired thymocyte development resulting in severe T cell lymphopenia. Additionally, we show that NFATc1 activity suppressed the B-lineage potential of immature thymocytes, and consolidated their differentiation to T cells. Further, in the pTCR-positive DN3 cells, a threshold level of NFATc1 activity was vital in facilitating T cell differentiation and to prevent T-acute lymphoblastic leukemia (T-ALL) development. Altogether, our results show NFATc1 activity is crucial in determining the T cell fate of thymocytes. Overall design: ChIP-seq for H3K27ac was performed from DRag thymocytes