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The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia.

Recent studies have shown that activating mutations of NOTCH1 are responsible for the majority of T cell acute lymphoblastic leukemia (T-ALL) cases. Most of these mutations truncate its C-terminal domain, a region that is important for the NOTCH1 proteasome-mediated degradation. We report that the E3 ligase FBW7 targets NOTCH1 for ubiquitination and degradation. Our studies map in detail the amino acid degron sequence required for NOTCH1-FBW7 interaction. Furthermore, we identify inactivating FBW7 mutations in a large fraction of human T-ALL lines and primary leukemias. These mutations abrogate the binding of FBW7 not only to NOTCH1 but also to the two other characterized targets, c-Myc and cyclin E. The majority of the FBW7 mutations were present during relapse, and they were associated with NOTCH1 HD mutations. Interestingly, most of the T-ALL lines harboring FBW7 mutations were resistant to gamma-secretase inhibitor treatment and this resistance appeared to be related to the stabilization of the c-Myc protein. Our data suggest that FBW7 is a novel tumor suppressor in T cell leukemia, and implicate the loss of FBW7 function as a potential mechanism of drug resistance in T-ALL.

Pubmed ID: 17646408


  • Thompson BJ
  • Buonamici S
  • Sulis ML
  • Palomero T
  • Vilimas T
  • Basso G
  • Ferrando A
  • Aifantis I


The Journal of experimental medicine

Publication Data

August 6, 2007

Associated Grants

  • Agency: NCI NIH HHS, Id: CA120196
  • Agency: NCI NIH HHS, Id: R01 CA120196
  • Agency: NCI NIH HHS, Id: R01 CA120196-02
  • Agency: NCI NIH HHS, Id: R01CA105129

Mesh Terms

  • Amyloid Precursor Protein Secretases
  • Cell Cycle Proteins
  • F-Box Proteins
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor
  • Humans
  • Leukemia, T-Cell
  • Microscopy, Fluorescence
  • Mutation
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Protein Binding
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-myc
  • Receptor, Notch1
  • Stem Cell Factor
  • Ubiquitin-Protein Ligases