Targeting the NF-kappaB signaling pathway in Notch1-induced T-cell leukemia.

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-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.

• Authors: 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
• Journal: Nature medicine (Nat Med) Vol. 13 Issue 1 Pg. 70-7 (Jan 2007) ISSN: 1078-8956 [Print] United States
• PMID: 17173050 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Boronic Acids
• CD4 Antigens
• CD8 Antigens
• DNA-Binding Proteins
• Il2rg protein, mouse
• Interleukin Receptor Common gamma Subunit
• NF-kappa B
• NOTCH1 protein, human
• Pyrazines
• Rag2 protein, mouse
• Receptor, Notch1
• Green Fluorescent Proteins
• Bortezomib

Topics

• Animals
• Boronic Acids (pharmacology)
• Bortezomib
• CD4 Antigens (analysis)
• CD8 Antigens (analysis)
• COS Cells
• Cell Line
• Cell Line, Tumor
• Cell Survival (drug effects)
• Chlorocebus aethiops
• DNA-Binding Proteins (genetics)
• Gene Expression Profiling
• Green Fluorescent Proteins (genetics, metabolism)
• Humans
• Interleukin Receptor Common gamma Subunit (genetics)
• Leukemia, Experimental (genetics, metabolism, pathology)
• Leukemia, T-Cell (genetics, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microscopy, Confocal
• Mutation
• NF-kappa B (metabolism)
• Pyrazines (pharmacology)
• Receptor, Notch1 (genetics, metabolism)
• Signal Transduction (genetics, physiology)
• Survival Analysis