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The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia
Benjamin J Thompson1, Silvia Buonamici, Maria Luisa Sulis
1Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
Abstract:
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.
Insights
The E3 ligase FBW7 targets NOTCH1 for degradation in T cell acute lymphoblastic leukemia (T-ALL). Inactivating FBW7 mutations are found in T-ALL, leading to drug resistance and suggesting FBW7 is a tumor suppressor.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Activating NOTCH1 mutations drive most T cell acute lymphoblastic leukemia (T-ALL) cases.
- These mutations often truncate NOTCH1, affecting its degradation.
- The C-terminal domain of NOTCH1 is crucial for its proteasomal degradation.
Purpose of the Study:
- To investigate the role of the E3 ligase FBW7 in NOTCH1 degradation.
- To identify FBW7 mutations in T-ALL and assess their functional consequences.
- To explore the link between FBW7 mutations, NOTCH1, c-Myc, cyclin E, and drug resistance in T-ALL.
Main Methods:
- Mapping the amino acid degron sequence for NOTCH1-FBW7 interaction.
- Screening human T-ALL cell lines and primary leukemias for FBW7 mutations.
- Analyzing the effect of FBW7 mutations on NOTCH1, c-Myc, and cyclin E binding.
- Assessing drug resistance in T-ALL lines with FBW7 mutations, particularly to gamma-secretase inhibitors.
Main Results:
- FBW7 directly targets NOTCH1 for ubiquitination and proteasomal degradation.
- Inactivating FBW7 mutations were identified in a significant proportion of T-ALL samples.
- These mutations impaired FBW7 binding to NOTCH1, c-Myc, and cyclin E.
- FBW7 mutations, often found at relapse and associated with NOTCH1 mutations, conferred resistance to gamma-secretase inhibitors, linked to c-Myc stabilization.
Conclusions:
- FBW7 acts as a tumor suppressor in T cell leukemia by degrading NOTCH1.
- Loss of FBW7 function contributes to T-ALL development and progression.
- FBW7 mutations represent a mechanism of drug resistance in T-ALL, particularly to gamma-secretase inhibitors.
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