The Notch/Hes1 Pathway Sustains NF-kappa B Activation through CYLD Repression in T Cell Leukemia
Por:
Espinosa, L, Cathelin, S, D'Altri, T, Trimarchi, T, Statnikov, A, Guiu, J, Rodilla, V, Ingles-Esteve, J, Nomdedeu, J, Bellosillo, B, Besses, C, Abdel-Wahab, O, Kucine, N, Sun, SC, Song, GC, Mullighan, CC, Levine, RL, Rajewsky, K, Aifantis, I, Bigas, A
Publicada:
14 sep 2010
Resumen:
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.
Filiaciones:
Espinosa, L:
Hosp del Mar, IMIM, Canc Res Program, Barcelona 08003, Spain
Cathelin, S:
NYU, Sch Med, Howard Hughes Med Inst, New York, NY 10016 USA
D'Altri, T:
Hosp del Mar, IMIM, Canc Res Program, Barcelona 08003, Spain
Trimarchi, T:
NYU, Sch Med, Howard Hughes Med Inst, New York, NY 10016 USA
Statnikov, A:
NYU, Sch Med, Dept Pathol, New York, NY 10016 USA
NYU, Sch Med, Ctr Hlth Informat & Bioinformat, New York, NY 10016 USA
NYU, Sch Med, Dept Med, New York, NY 10016 USA
Guiu, J:
Hosp del Mar, IMIM, Canc Res Program, Barcelona 08003, Spain
Rodilla, V:
Hosp del Mar, IMIM, Canc Res Program, Barcelona 08003, Spain
Ingles-Esteve, J:
Hosp del Mar, IMIM, Canc Res Program, Barcelona 08003, Spain
Nomdedeu, J:
Hosp Santa Creu & Sant Pau, Dept Hematol, Barcelona 08025, Spain
Bellosillo, B:
Hosp del Mar, Dept Pathol, Barcelona 08003, Spain
Besses, C:
Hosp del Mar, Dept Hematol, Barcelona 08003, Spain
Abdel-Wahab, O:
Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA
Kucine, N:
Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA
Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10065 USA
Sun, SC:
Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA
Song, GC:
St Judes Res Hosp, Dept Pathol, Memphis, TN 38105 USA
Mullighan, CC:
St Judes Res Hosp, Dept Pathol, Memphis, TN 38105 USA
Levine, RL:
Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA
Rajewsky, K:
Harvard Univ, Sch Med, Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA
Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA
Aifantis, I:
NYU, Sch Med, Howard Hughes Med Inst, New York, NY 10016 USA
Bigas, A:
Hosp del Mar, IMIM, Canc Res Program, Barcelona 08003, Spain
Green Accepted
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