The Notch/Hes1 Pathway Sustains NF-I[ordmB Activation through CYLD Repression in T Cell Leukemia

• Published in: Cancer cell 2010-09, Vol.18 (3), p.268-281
• Main Authors: Espinosa, Lluis, Cathelin, Severine, D'Altri, Teresa, Trimarchi, Thomas, Statnikov, Alexander, Guiu, Jordi, Rodilla, Veronica, Ingles-Esteve, Julia, Nomdedeu, Josep, Bellosillo, Beatriz, Besses, Carles, Abdel-Wahab, Omar, Kucine, Nicole, Sun, Shao-Cong, Song, Guangchan, Mullighan, Charles C, Levine, Ross L, Rajewsky, Klaus, Aifantis, Iannis, Bigas, Anna
• Format: Article
• Language: English
• ISSN: 1535-6108
• DOI: 10.1016/j.ccr.2010.08.006

It was previously shown that the NF-I[ordmB pathway is downstream of oncogenic Notch1 in Taacell acute lymphoblastic leukemia (T-ALL). Here, we visualize Notch-induced NF-I[ordmB 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 inaavivo. a-[ordm NF-I[ordmB activity is active and essential in established Notch-dependent T-ALL leukemias a-[ordm Notch through Hes1 sustains NF-I[ordmB activity by repressing the deubiquitinase CYLD a-[ordm Inhibition of IKK/NFI[ordmB activity reduces leukemic load and increases survival in mice