Targeting the NF-kappa B 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-kappa B pathway transcriptionally and via the I kappa B kinase (IKK) complex, thereby causing increased expression of several well characterized target genes of NF-kappa B in bone marrow hematopoietic stem cells and progenitors. Our observations demonstrate that the NF-kappa B 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-kappa B as one of the major mediators of Notch1-induced transformation and suggest that the NF-kappa B pathway is a potential target of future therapies of T-ALL.