Targeting the NF-kappaB signaling pathway in Notch1-induced T-cell leukemia.
T-cell acute lymphoblastic leukemia (T-ALL), unlike other ALL types, is only infrequently associated with chromosomal aberrations, but it was recently shown that most individuals with T-ALL carry activating mutations in the NOTCH1 gene. However, the signaling pathways and target genes responsible for Notch1-induced neoplastic transformation remain undefined. We report here that constitutively active Notch1 activates the NF-kappaB pathway transcriptionally and via the IkappaB kinase (IKK) complex, thereby causing increased expression of several well characterized target genes of NF-kappaB in bone marrow hematopoietic stem cells and progenitors. Our observations demonstrate that the NF-kappaB pathway is highly active in established human T-ALL and that inhibition of the pathway can efficiently restrict tumor growth both in vitro and in vivo. These findings identify NF-kappaB as one of the major mediators of Notch1-induced transformation and suggest that the NF-kappaB pathway is a potential target of future therapies of T-ALL.
Vilimas
Tomas
T
Department of Medicine, Section of Rheumatology, University of Chicago, 5841 South Maryland Avenue Chicago, Illinois 60637, USA.
Mascarenhas
Joaquina
J
Palomero
Teresa
T
Mandal
Malay
M
Buonamici
Silvia
S
Meng
Fanyong
F
Thompson
Benjamín
B
Spaulding
Christina
C
Macaroun
Sami
S
Alegre
Maria-Luisa
ML
Kee
Barbara L
BL
Ferrando
Adolfo
A
Miele
Lucio
L
Aifantis
Iannis
I
D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D019556:COS Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000235:genetics; D020869:Gene Expression Profiling; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D007942:Leukemia, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015458:Leukemia, T-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D016019:Survival Analysis
D001897:Boronic Acids; D015704:CD4 Antigens; D016827:CD8 Antigens; D004268:DNA-Binding Proteins; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D016328:NF-kappa B; C497761:NOTCH1 protein, human; D011719:Pyrazines; C499308:Rag2 protein, mouse; D051881:Receptor, Notch1; D049452:Green Fluorescent Proteins; D000069286:Bortezomib