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 γ-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.
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6 August 2007
Article|
July 23 2007
The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia
Benjamin J. Thompson,
Benjamin J. Thompson
1Department of Pathology
2New York University Cancer Institute, New York University School of Medicine, New York, NY 10016
3Medical Scientist Training Program, Committee on Immunology, University of Chicago, Chicago, IL 60637
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Silvia Buonamici,
Silvia Buonamici
1Department of Pathology
2New York University Cancer Institute, New York University School of Medicine, New York, NY 10016
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Maria Luisa Sulis,
Maria Luisa Sulis
4Institute for Cancer Genetics, Columbia University, New York, NY 10032
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Teresa Palomero,
Teresa Palomero
4Institute for Cancer Genetics, Columbia University, New York, NY 10032
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Tomas Vilimas,
Tomas Vilimas
5Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611
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Giuseppe Basso,
Giuseppe Basso
6Hemato-Oncology Laboratory, Department of Pediatrics, University of Padova, 35122 Padova, Italy
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Adolfo Ferrando,
Adolfo Ferrando
4Institute for Cancer Genetics, Columbia University, New York, NY 10032
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Iannis Aifantis
Iannis Aifantis
1Department of Pathology
2New York University Cancer Institute, New York University School of Medicine, New York, NY 10016
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Benjamin J. Thompson
1Department of Pathology
2New York University Cancer Institute, New York University School of Medicine, New York, NY 10016
3Medical Scientist Training Program, Committee on Immunology, University of Chicago, Chicago, IL 60637
Silvia Buonamici
1Department of Pathology
2New York University Cancer Institute, New York University School of Medicine, New York, NY 10016
Maria Luisa Sulis
4Institute for Cancer Genetics, Columbia University, New York, NY 10032
Teresa Palomero
4Institute for Cancer Genetics, Columbia University, New York, NY 10032
Tomas Vilimas
5Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611
Giuseppe Basso
6Hemato-Oncology Laboratory, Department of Pediatrics, University of Padova, 35122 Padova, Italy
Adolfo Ferrando
4Institute for Cancer Genetics, Columbia University, New York, NY 10032
Iannis Aifantis
1Department of Pathology
2New York University Cancer Institute, New York University School of Medicine, New York, NY 10016
CORRESPONDENCE Iannis Aifantis: [email protected]
Abbreviations used: AML, acute myeloid leukemia; DN, dominant-negative; GSI, γ-secretase inhibitors; HD, heterodimerization; T-ALL, T cell acute lymphoblastic leukemia.
B.J. Thompson and S. Buonamici contributed equally to this paper.
Received:
May 01 2007
Accepted:
June 28 2007
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2007
J Exp Med (2007) 204 (8): 1825–1835.
Article history
Received:
May 01 2007
Accepted:
June 28 2007
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New mutations stabilize NOTCH1
Citation
Benjamin J. Thompson, Silvia Buonamici, Maria Luisa Sulis, Teresa Palomero, Tomas Vilimas, Giuseppe Basso, Adolfo Ferrando, Iannis Aifantis; The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia . J Exp Med 6 August 2007; 204 (8): 1825–1835. doi: https://doi.org/10.1084/jem.20070872
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