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¹ Department of Pathology, ² New York University Cancer Institute, New York University School of Medicine, New York, NY 10016
³ Medical Scientist Training Program, Committee on Immunology, University of Chicago, Chicago, IL 60637
⁴ Institute for Cancer Genetics, Columbia University, New York, NY 10032
⁵ Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611
⁶ Hemato-Oncology Laboratory, Department of Pediatrics, University of Padova, 35122 Padova, Italy

CORRESPONDENCE Iannis Aifantis: iannis.aifantis{at}med.nyu.edu

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 -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.

Abbreviations used: AML, acute myeloid leukemia; DN, dominant-negative; GSI, -secretase inhibitors; HD, heterodimerization; T-ALL, T cell acute lymphoblastic leukemia.

B.J. Thompson and S. Buonamici contributed equally to this paper.

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