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.
Thompson
Benjamin J
BJ
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
Buonamici
Silvia
S
Sulis
Maria Luisa
ML
Palomero
Teresa
T
Vilimas
Tomas
T
Basso
Giuseppe
G
Ferrando
Adolfo
A
Aifantis
Iannis
I
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D018797:Cell Cycle Proteins / Q000378:metabolism*; D044783:F-Box Proteins / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D015458:Leukemia, T-Cell / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism; D019089:Stem Cell Factor / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism
D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C497761:NOTCH1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D051881:Receptor, Notch1; D019089:Stem Cell Factor; D044767:Ubiquitin-Protein Ligases; D053829:Amyloid Precursor Protein Secretases