The Notch/Hes1 pathway sustains NF-κB activation through CYLD repression in T cell leukemia.
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.
Espinosa
Lluis
L
Cancer Research Program, Institut Municipal d'Investigacions Mèdiques, (IMIM), Hospital del Mar, 08003 Barcelona, Spain. lespinosa@imim.es
Cathelin
Severine
S
D'Altri
Teresa
T
Trimarchi
Thomas
T
Statnikov
Alexander
A
Guiu
Jordi
J
Rodilla
Veronica
V
Inglés-Esteve
Julia
J
Nomdedeu
Josep
J
Bellosillo
Beatriz
B
Besses
Carles
C
Abdel-Wahab
Omar
O
Kucine
Nicole
N
Sun
Shao-Cong
SC
Song
Guangchan
G
Mullighan
Charles C
CC
Levine
Ross L
RL
Rajewsky
Klaus
K
Aifantis
Iannis
I
Bigas
Anna
A
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
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