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.
authors.affiliation: Cancer Research Program, Institut Municipal d'Investigacions Mèdiques, (IMIM), Hospital del Mar, 08003 Barcelona, Spain. lespinosa@imim.es
authors.forename: Lluis
authors.initials: L
authors.lastname: Espinosa
authors.forename: Severine
authors.initials: S
authors.lastname: Cathelin
authors.forename: Teresa
authors.initials: T
authors.lastname: D'Altri
authors.forename: Thomas
authors.initials: T
authors.lastname: Trimarchi
authors.forename: Alexander
authors.initials: A
authors.lastname: Statnikov
authors.forename: Jordi
authors.initials: J
authors.lastname: Guiu
authors.forename: Veronica
authors.initials: V
authors.lastname: Rodilla
authors.forename: Julia
authors.initials: J
authors.lastname: Inglés-Esteve
authors.forename: Josep
authors.initials: J
authors.lastname: Nomdedeu
authors.forename: Beatriz
authors.initials: B
authors.lastname: Bellosillo
authors.forename: Carles
authors.initials: C
authors.lastname: Besses
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.forename: Nicole
authors.initials: N
authors.lastname: Kucine
authors.forename: Shao-Cong
authors.initials: SC
authors.lastname: Sun
authors.forename: Guangchan
authors.initials: G
authors.lastname: Song
authors.forename: Charles C
authors.initials: CC
authors.lastname: Mullighan
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: Klaus
authors.initials: K
authors.lastname: Rajewsky
authors.forename: Iannis
authors.initials: I
authors.lastname: Aifantis
authors.forename: Anna
authors.initials: A
authors.lastname: Bigas
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D000074749:Deubiquitinating Enzyme CYLD; D016147:Genes, Tumor Suppressor; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015458:Leukemia, T-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000072056:Transcription Factor HES-1; D051996:Transcription Factor RelA / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000074749:Deubiquitinating Enzyme CYLD; D018398:Homeodomain Proteins; D016328:NF-kappa B; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; D051996:Transcription Factor RelA; D025521:Tumor Suppressor Proteins; C078493:HES1 protein, human; C409984:CYLD protein, human