title: Evidence of an oncogenic role of aberrant TOX activation in cutaneous T-cell lymphoma.
abstract: TOX is a nuclear factor essential for the development of CD4(+) T cells in the thymus. It is normally expressed in low amounts in mature CD4(+) T cells of the skin and the peripheral blood. We have recently discovered that the transcript levels of TOX were significantly increased in mycosis fungoides, the most common type of cutaneous T-cell lymphoma (CTCL), as compared to normal skin or benign inflammatory dermatoses. However, its involvement in advanced CTCL and its biological effects on CTCL pathogenesis have not been explored. In this study, we demonstrate that TOX expression is also enhanced significantly in primary CD4(+)CD7(-) cells from patients with Sézary syndrome, a leukemic variant of CTCL, and that high TOX transcript levels correlate with increased disease-specific mortality. Stable knockdown of TOX in CTCL cells promoted apoptosis and reduced cell cycle progression, leading to less cell viability and colony-forming ability in vitro and to reduced tumor growth in vivo. Furthermore, TOX knockdown significantly increased 2 cyclin-dependent kinase (CDK) inhibitors, CDKN1B and CDKN1C. Lastly, blocking CDKN1B and CDKN1C reversed growth inhibition of TOX knockdown. Collectively, these findings provide strong evidence that aberrant TOX activation is a critical oncogenic event for CTCL.
authors.affiliation: Molecular Medicine Laboratory, Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada; Chieng Genomics Center, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada; Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Yuanshen
authors.identifier: http://orcid.org/0000-0003-4603-1294
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Molecular Medicine Laboratory, Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada; Chieng Genomics Center, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada;
authors.forename: Ming-Wan
authors.initials: MW
authors.lastname: Su
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; and.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Molecular Medicine Laboratory, Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada; Chieng Genomics Center, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada; Dermatologic Oncology Program, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Youwen
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D016022:Case-Control Studies; D049109:Cell Proliferation; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006609:High Mobility Group Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012751:Sezary Syndrome / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D012878:Skin Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57; D006609:High Mobility Group Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C558851:TOX protein, human