Targeting the NF-?B signaling pathway in Notch1-induced T cell leukemia. Mus musculus

T cell acute lymphoblastic leukemia (T-ALL), unlike other ALL types, is only infrequently associated with chromosomal aberrations, but it was recently shown that the majority of TALL patients 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-?B pathway transcriptionally and via the I?B kinase (IKK) complex, thereby causing increased expression of multiple well-characterized NF-?B target genes in bone marrow hematopoietic stem cells and progenitors. Our observations demonstrate that the NF-?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 studies identify NF-?B as one of the major mediators of NOTCH1-induced transformation and suggest that the NF-?B pathway is a potential target of future targeted therapies of T-ALL. Keywords: gene expression analysis, signaling pathway alteration Overall design: Number of samples: 2. Replicates: no. Dye swaps: yes (Cy3, Cy5). Reference sample: 1.