Oncogenic mutations in the FBXW7 gene of adult T-cell leukemia patients.
Human T-cell leukemia virus type 1 (HTLV-I) is associated with adult T-cell leukemia (ATL), an aggressive lymphoproliferative disease with a dismal prognosis. We have previously described the presence of Notch1 activating mutations and constitutive Notch1 signaling in patients with acute ATL. In this study, we report a high frequency of ... F-box and WD repeat domain containing 7 (FBXW7)/hCDC4 mutations within the WD40 substrate-binding domain in 8 of 32 acute ATL patients (25%). Functionally, ATL FBXW7 mutants lost their ability to interact with intracellular Notch (NICD), resulting in increased protein stability and constitutive Notch1 signaling. Consistent with the loss-of-function found in ATL patients, expression of WT FBXW7 in several patient-derived ATL lines demonstrated strong tumor-suppressor activity characterized by reduced proliferation of ATL cells. Remarkably, two FBXW7 mutants, D510E and D527G, demonstrated oncogenic activity when expressed in the presence of HTLV-I Tax, mutated p53 R276H, or c-Myc F138C found in human cancers. Transforming activity was further demonstrated by the ability of the FBXW7 D510E mutant to provide IL-2-independent growth of Tax-immortalized human T cells and increase the tumor formation in a xenograft mouse model of ATL. This study suggests that FBXW7, normally a tumor suppressor, can act as an oncogene when mutated and may play an important role in the pathogenesis of ATL.
Mesh Terms:
Adult, Amino Acid Substitution, Animals, Cell Cycle Proteins, Cell Line, Tumor, F-Box Proteins, Female, Heterografts, Human T-lymphotropic virus 1, Humans, Interleukin-2, Leukemia-Lymphoma, Adult T-Cell, Male, Mice, Mice, Nude, Mutation, Missense, Neoplasm Transplantation, Protein Domains, Proto-Oncogene Proteins c-myc, Rats, Receptor, Notch1, Signal Transduction, Ubiquitin-Protein Ligases
Adult, Amino Acid Substitution, Animals, Cell Cycle Proteins, Cell Line, Tumor, F-Box Proteins, Female, Heterografts, Human T-lymphotropic virus 1, Humans, Interleukin-2, Leukemia-Lymphoma, Adult T-Cell, Male, Mice, Mice, Nude, Mutation, Missense, Neoplasm Transplantation, Protein Domains, Proto-Oncogene Proteins c-myc, Rats, Receptor, Notch1, Signal Transduction, Ubiquitin-Protein Ligases
Proc. Natl. Acad. Sci. U.S.A.
Date: Dec. 14, 2015
PubMed ID: 27247421
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