The Notch/Hes1 pathway sustains NF-B activation through CYLD repression in T cell leukemia

The NF-B pathway is a critical regulator of the immune system and has been implicated in cellular transformation and tumorigenesis. NF-B response is regulated by the activation state of the IB kinase (IKK) complex and triggered by a wide spectrum of stimuli. We previously reported that NF-B is downstream of Notch1 in T cell acute lymphoblastic leukaemia (T-ALL), however both the mechanisms involving Notch1-induced NF-B activation and the potential importance of NF-B in the maintenance of the disease are unknown. Here we visualize Notch-induced NF-B activation using both human T-ALL cell lines and animal models of this type of leukemia. We show that it is not Notch1 itself but Hes1, a canonical Notch target, the responsible for sustaining IKK activation in T-ALL. Hes1 exerts its effects by a direct transcriptional repression of the deubiquitinating enzyme CYLD, a well-characterized IKK inhibitor. Consistently, CYLD expression is significantly reduced in primary T-ALL leukemias. Finally, we demonstrate that IKK complex inhibition is a promising option for the targeted therapy of T-ALL as suppression of IKK function affected both the survival of human T-ALL cells in vitro and the maintenance of the disease in vivo.

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Espinosa L, Cathelin S, D'Altri T, Trimarchi T, Statnikov A, Guiu J, Rodilla V, Inglés-Esteve J, Nomdedeu J, Bellosillo B, Besses C, Abdel-Wahab O, Kucine N, Sun SC, Song G, Mullighan CC, Levine RL, Rajewsky K, Aifantis I, Bigas A