Author: ["Tomas Vilimas","Joaquina Mascarenhas","Teresa Palomero","Malay Mandal","Silvia Buonamici","Fanyong Meng","Benjamín Thompson","Christina Spaulding","Sami Macaroun","Maria-Luisa Alegre","Barbara L Kee","Adolfo Ferrando","Lucio Miele","Iannis Aifantis"]
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Abstract
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-κB pathway transcriptionally and via the IκB kinase (IKK) complex, thereby causing increased expression of several well characterized target genes of NF-κB in bone marrow hematopoietic stem cells and progenitors. Our observations demonstrate that the NF-κB 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-κB as one of the major mediators of Notch1-induced transformation and suggest that the NF-κB pathway is a potential target of future therapies of T-ALL.Cite this article
Vilimas, T., Mascarenhas, J., Palomero, T. et al. Targeting the NF-κB signaling pathway in Notch1-induced T-cell leukemia. Nat Med 13, 70–77 (2007). https://doi.org/10.1038/nm1524 