title: Oncogenic mutations in the FBXW7 gene of adult T-cell leukemia patients.
abstract: 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.
authors.affiliation: Department of Pathology, Center for Viral Oncology, University of Kansas Medical Center, Kansas City, KS 66160.
authors.forename: Chien-Hung
authors.initials: CH
authors.lastname: Yeh
authors.affiliation: Department of Pathology, Center for Viral Oncology, University of Kansas Medical Center, Kansas City, KS 66160.
authors.forename: Marcia
authors.initials: M
authors.lastname: Bellon
authors.affiliation: Department of Pathology, Center for Viral Oncology, University of Kansas Medical Center, Kansas City, KS 66160.
authors.forename: Joanna
authors.initials: J
authors.lastname: Pancewicz-Wojtkiewicz
authors.affiliation: Department of Pathology, Center for Viral Oncology, University of Kansas Medical Center, Kansas City, KS 66160 cnicot@kumc.edu.
authors.forename: Christophe
authors.initials: C
authors.lastname: Nicot
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D044783:F-Box Proteins / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D064593:Heterografts; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D020125:Mutation, Missense; D009368:Neoplasm Transplantation; D000072417:Protein Domains; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D051381:Rats; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C508594:IL2 protein, human; D007376:Interleukin-2; C489427:MYC protein, human; C497761:NOTCH1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D051881:Receptor, Notch1; D044767:Ubiquitin-Protein Ligases
keywords: FBXW7; HTLV; Notch; leukemia; oncogene