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.
Author(s): Tomas Vilimas [1, 6, 7]; Joaquina Mascarenhas [2, 6]; Teresa Palomero [3]; Malay Mandal [1]; Silvia Buonamici [1, 4]; Fanyong Meng [1]; Benjamin Thompson [1, 4]; Christina Spaulding [5]; [...]