Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/25855
Title: A genetic IFN/STAT1/FAS axis determines CD4 T stem cell memory levels and apoptosis in healthy controls and Adult T-cell Leukemia patients
Authors: Khouri, Antonio Ricardo
Santos, Gilvanéia Silva
Dierckx, Tim
Menezes, Soraya Maria
Decanine, Daniele
Theys, Kristof
Silva, Aline Clara
Vallve, Maria Lourdes Farré
Bittencourt, Achiléa Candida Lisboa
Mangino, Massimo
Roederer, Mario
Vandamme, Anne-Mieke
Weyenbergh, Johan Van
Affilliation: University of Leuven. Rega Institute for Medical Research. Department of Microbiology and Immunology. Clinical and Epidemiological Virology. KU Leuven. Leuven, Belgium / Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil
University of Leuven. Rega Institute for Medical Research. Department of Microbiology and Immunology. Clinical and Epidemiological Virology. KU Leuven. Leuven, Belgium
University of Leuven. Rega Institute for Medical Research. Department of Microbiology and Immunology. Clinical and Epidemiological Virology. KU Leuven. Leuven, Belgium
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil
University of Leuven. Rega Institute for Medical Research. Department of Microbiology and Immunology. Clinical and Epidemiological Virology. KU Leuven. Leuven, Belgium
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil
Universidade Federal da Bahia. Complexo Hospitalar Universit ario Prof Edgard Santos. Departamento de Pathologia. Salvador, BA, Brasil
King’s College. Department of Twin Research & Genetic Epidemiology. London, UK
National Institute of Allergy and Infectious Diseases. Vaccine Research Center. Immunotechnology Section. Bethesda, MD, USA
University of Leuven. Rega Institute for Medical Research. Department of Microbiology and Immunology. Clinical and Epidemiological Virology. KU Leuven. Leuven, Belgium / Universidade Nova de Lisboa. Instituto de Highne e Medicina Tropical. Center for Global Health and Tropical Medicine. Unidade de Microbiologia. Lisbon,
University of Leuven. Rega Institute for Medical Research. Department of Microbiology and Immunology. Clinical and Epidemiological Virology. KU Leuven. Leuven, Belgium
Abstract: Adult T-cell leukemia (ATL) is an aggressive, chemotherapy-resistant CD4CCD25C leukemia caused by HTLV-1 infection, which usually develops in a minority of patients several decades after infection. IFN C AZT combination therapy has shown clinical benefit in ATL, although its mechanism of action remains unclear. We have previously shown that an IFN-responsive FAS promoter polymorphism in a STAT1 binding site (rs1800682) is associated to ATL susceptibility and survival. Recently, CD4 T stem cell memory (TSCM) Fashi cells have been identified as the hierarchical cellular apex of ATL, but a possible link between FAS, apoptosis, proliferation and IFN response in ATL has not been studied. In this study, we found significant ex vivo antiproliferative, antiviral and immunomodulatory effects of IFN-a treatment in short-term culture of primary mononuclear cells from ATL patients (n D 25). Bayesian Network analysis allowed us to integrate ex vivo IFN-a response with clinical, genetic and immunological data from ATL patients, thereby revealing a central role for FAS -670 polymorphism and apoptosis in the coordinated mechanism of action of IFN-a. FAS genotype-dependence of IFN-induced apoptosis was experimentally validated in an independent cohort of healthy controls (n D 20). The same FAS -670 polymorphism also determined CD4 TSCM levels in a genome-wide twin study (p D 7 £ 10¡11, n D 460), confirming a genetic link between apoptosis and TSCM levels. Transcriptomic analysis and cell type deconvolution confirmed the FAS genotype/TSCM link and IFN-a-induced downregulation of CD4 TSCMspecific genes in ATL patient cells. In conclusion, ex vivo IFN-a treatment exerts a pleiotropic effect on primary ATL cells, with a genetic IFN/STAT1/Fas axis determining apoptosis vs. proliferation and underscoring the CD4 TSCM model of ATL leukemogenesis.
Keywords: CD95
HTLV-1
Genetics
Interferon
Leukemia
Lymphoma
Oncogenesis
keywords: CD95
HTLV-1
Genética
Interferon
Leucemia
Linfoma
Oncogênese
Issue Date: 2018
Publisher: Taylor & Francis
Citation: KHOURI, A. R. et al. A genetic IFN/STAT1/FAS axis determines CD4 T stem cell memory levels and apoptosis in healthy controls and Adult T-cell Leukemia patients. OncoImmunology, e1426423, 2018.
ISSN: 2162-4011
Copyright: open access
Appears in Collections:BA - IGM - Artigos de Periódicos

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