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Cancer Cell. 2010 Sep 14;18(3):268-81. doi: 10.1016/j.ccr.2010.08.006.

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

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  • 1Cancer Research Program, Institut Municipal d'Investigacions Mèdiques, (IMIM), Hospital del Mar, 08003 Barcelona, Spain.


It was 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.

Copyright © 2010 Elsevier Inc. All rights reserved.

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