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

Nat Med. 2007 Jan;13(1):70-7. doi: 10.1038/nm1524. Epub 2006 Dec 17.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Interleukin Receptor Common gamma Subunit / genetics
  • Leukemia, Experimental / genetics
  • Leukemia, Experimental / metabolism
  • Leukemia, Experimental / pathology
  • Leukemia, T-Cell / genetics
  • Leukemia, T-Cell / metabolism
  • Leukemia, T-Cell / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Confocal
  • Mutation
  • NF-kappa B / metabolism*
  • Pyrazines / pharmacology
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Survival Analysis

Substances

  • 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