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

被引：250

作者：

Espinosa, Lluis ^{[1
]}

Cathelin, Severine ^{[2
]}

D'Altri, Teresa ^{[1
]}

Trimarchi, Thomas ^{[2
]}

Statnikov, Alexander ^{[3
,4
,5
]}

Guiu, Jordi ^{[1
]}

Rodilla, Veronica ^{[1
]}

Ingles-Esteve, Julia ^{[1
]}

Nomdedeu, Josep ^{[6
]}

Bellosillo, Beatriz ^{[7
]}

Besses, Carles ^{[8
]}

Abdel-Wahab, Omar ^{[9
]}

Kucine, Nicole ^{[9
,10
]}

Sun, Shao-Cong ^{[11
]}

Song, Guangchan ^{[12
]}

Mullighan, Charles C. ^{[12
]}

Levine, Ross L. ^{[9
]}

Rajewsky, Klaus ^{[13
,14
]}

Aifantis, Iannis ^{[2
]}

Bigas, Anna ^{[1
]}

机构：

[1] Hosp del Mar, IMIM, Canc Res Program, Barcelona 08003, Spain

[2] NYU, Sch Med, Howard Hughes Med Inst, New York, NY 10016 USA

[3] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA

[4] NYU, Sch Med, Ctr Hlth Informat & Bioinformat, New York, NY 10016 USA

[5] NYU, Sch Med, Dept Med, New York, NY 10016 USA

[6] Hosp Santa Creu & Sant Pau, Dept Hematol, Barcelona 08025, Spain

[7] Hosp del Mar, Dept Pathol, Barcelona 08003, Spain

[8] Hosp del Mar, Dept Hematol, Barcelona 08003, Spain

[9] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[10] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10065 USA

[11] Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA

[12] St Judes Res Hosp, Dept Pathol, Memphis, TN 38105 USA

[13] Harvard Univ, Sch Med, Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA

[14] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA

来源：

CANCER CELL | 2010年 / 18卷 / 03期

基金：

美国国家卫生研究院;

关键词：

DEUBIQUITINATING ENZYME CYLD; SIGNALING PATHWAY; MULTIPLE-MYELOMA; TRANSCRIPTION FACTORS; KINASE TAK1; IN-VIVO; NOTCH1; GENE; MUTATIONS; LYMPHOMA;

D O I：

10.1016/j.ccr.2010.08.006

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

It was previously shown that the NF-kappa B pathway is downstream of oncogenic Notch1 in T cell acute lymphoblastic leukemia (T-ALL). Here, we visualize Notch-induced NF-kappa B 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.

引用

页码：268 / 281

页数：14

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