Author/Authors :
Espinosa، نويسنده , , Lluis and Cathelin، نويسنده , , Severine and DʹAltri، نويسنده , , Teresa and Trimarchi، نويسنده , , Thomas and Statnikov، نويسنده , , Alexander and Guiu، نويسنده , , Jordi and Rodilla، نويسنده , , Veronica and Inglés-Esteve، نويسنده , , Julia and Nomdedeu، نويسنده , , Josep and Bellosillo، نويسنده , , Beatriz and Besses، نويسنده , , Carles and Abdel-Wahab، نويسنده , , Omar and Kucine، نويسنده , , Nicole and Sun، نويسنده , , Shao-Cong and Song، نويسنده , , Guangchan and Mullighan، نويسنده , , Charles C. and Levine، نويسنده , , Ross L. and Rajewsky، نويسنده , , Klaus and Aifantis، نويسنده , , Iannis and Bigas، نويسنده , , Anna، نويسنده ,
Abstract :
Summary
previously shown that the NF-κB pathway is downstream of oncogenic Notch1 in T cell acute lymphoblastic leukemia (T-ALL). Here, we visualize Notch-induced NF-κB activation using both human T-ALL cell lines and animal models. We demonstrate that Hes1, a canonical Notch target and transcriptional repressor, is responsible for sustaining IKK activation in T-ALL. Hes1 exerts its effects by repressing the deubiquitinase CYLD, a negative IKK complex regulator. CYLD expression was found to be significantly suppressed in primary T-ALL. Finally, we demonstrate that IKK inhibition is a promising option for the targeted therapy of T-ALL as specific suppression of IKK expression and function affected both the survival of human T-ALL cells and the maintenance of the disease in vivo.
