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

Lluis Espinosa; Severine Cathelin; Teresa D'Altri; Thomas Trimarchi; Alexander Statnikov; Jordi Guiu; Veronica Rodilla; Julia Inglés-Esteve; Josep Nomdedeu; Beatriz Bellosillo; Carles Besses; Omar Abdel-Wahab; Nicole Kucine; Shao Cong Sun; Guangchan Song; Charles C. Mullighan; Ross L. Levine; Klaus Rajewsky; Iannis Aifantis; Anna Bigas

doi:10.1016/j.ccr.2010.08.006

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

Lluis Espinosa, Severine Cathelin, Teresa D'Altri, Thomas Trimarchi, Alexander Statnikov, Jordi Guiu, Veronica Rodilla, Julia Inglés-Esteve, Josep Nomdedeu, Beatriz Bellosillo, Carles Besses, Omar Abdel-Wahab, Nicole Kucine, Shao Cong Sun, Guangchan Song, Charles C. Mullighan, Ross L. Levine, Klaus Rajewsky, Iannis Aifantis^*, Anna Bigas

^*Corresponding author af dette arbejde

198 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Cancer Cell
Vol/bind	18
Udgave nummer	3
Sider (fra-til)	268-281
Antal sider	14
ISSN	1535-6108
DOI	https://doi.org/10.1016/j.ccr.2010.08.006
Status	Udgivet - 1 jan. 2010
Udgivet eksternt	Ja

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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, S. C., Song, G., Mullighan, C. C., Levine, R. L., Rajewsky, K., Aifantis, I., & Bigas, A. (2010). The Notch/Hes1 pathway sustains NF-κB activation through CYLD repression in T cell leukemia. Cancer Cell, 18(3), 268-281. https://doi.org/10.1016/j.ccr.2010.08.006

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 2010, 'The Notch/Hes1 pathway sustains NF-κB activation through CYLD repression in T cell leukemia', Cancer Cell, bind 18, nr. 3, s. 268-281. https://doi.org/10.1016/j.ccr.2010.08.006

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title = "The Notch/Hes1 pathway sustains NF-κB activation through CYLD repression in T cell leukemia",

abstract = "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.",

author = "Lluis Espinosa and Severine Cathelin and Teresa D'Altri and Thomas Trimarchi and Alexander Statnikov and Jordi Guiu and Veronica Rodilla and Julia Ingl{\'e}s-Esteve and Josep Nomdedeu and Beatriz Bellosillo and Carles Besses and Omar Abdel-Wahab and Nicole Kucine and Sun, {Shao Cong} and Guangchan Song and Mullighan, {Charles C.} and Levine, {Ross L.} and Klaus Rajewsky and Iannis Aifantis and Anna Bigas",

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month = jan,

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doi = "10.1016/j.ccr.2010.08.006",

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T1 - The Notch/Hes1 pathway sustains NF-κB activation through CYLD repression in T cell leukemia

AU - Espinosa, Lluis

AU - Cathelin, Severine

AU - D'Altri, Teresa

AU - Trimarchi, Thomas

AU - Statnikov, Alexander

AU - Guiu, Jordi

AU - Rodilla, Veronica

AU - Inglés-Esteve, Julia

AU - Nomdedeu, Josep

AU - Bellosillo, Beatriz

AU - Besses, Carles

AU - Abdel-Wahab, Omar

AU - Kucine, Nicole

AU - Sun, Shao Cong

AU - Song, Guangchan

AU - Mullighan, Charles C.

AU - Levine, Ross L.

AU - Rajewsky, Klaus

AU - Aifantis, Iannis

AU - Bigas, Anna

PY - 2010/1/1

Y1 - 2010/1/1

N2 - 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.

AB - 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.

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U2 - 10.1016/j.ccr.2010.08.006

DO - 10.1016/j.ccr.2010.08.006

M3 - Journal article

C2 - 20832754

AN - SCOPUS:77956511912

SN - 1535-6108

VL - 18

SP - 268

EP - 281

JO - Cancer Cell

JF - Cancer Cell

IS - 3

ER -

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

Abstract

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