Author | Cunha, Antonio Ricardo Khouri | |
Author | Santos, Gilvanéia Silva | |
Author | Dierckx, Tim | |
Author | Menezes, Soraya Maria | |
Author | Decanine, Daniele | |
Author | Theys, Kristof | |
Author | Silva, Aline Clara | |
Author | Vallve, Maria Lourdes Farré | |
Author | Bittencourt, Achilea Candida Lisboa | |
Author | Mangino, Massimo | |
Author | Roederer, Mario | |
Author | Vandamme, Anne-Mieke | |
Author | Weyenbergh, Johan Van | |
Access date | 2018-04-16T14:19:05Z | |
Available date | 2018-04-16T14:19:05Z | |
Document date | 2018 | |
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. | pt_BR |
ISSN | 2162-4011 | pt_BR |
URI | https://www.arca.fiocruz.br/handle/icict/25855 | |
Sponsorship | Fonds Wetenschappelijk Onderzoek (G0D6817N) CNPq-FAPESB (PRONEX) VLAIO (PhD scholarship TD) Onderzoeksraad, KU Leuven (IRO) Onderzoeksraad, KU Leuven (Vaast Leysen Leerstoel) | pt_BR |
Language | eng | pt_BR |
Publisher | Taylor & Francis | pt_BR |
Rights | open access | pt_BR |
Subject in Portuguese | CD95 | pt_BR |
Subject in Portuguese | HTLV-1 | pt_BR |
Subject in Portuguese | Genética | pt_BR |
Subject in Portuguese | Interferon | pt_BR |
Subject in Portuguese | Leucemia | pt_BR |
Subject in Portuguese | Linfoma | pt_BR |
Subject in Portuguese | Oncogênese | pt_BR |
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 | pt_BR |
Type | Article | pt_BR |
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. | pt_BR |
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 | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil | pt_BR |
Affilliation | University of Leuven. Rega Institute for Medical Research. Department of Microbiology and Immunology. Clinical and Epidemiological Virology. KU Leuven. Leuven, Belgium | pt_BR |
Affilliation | University of Leuven. Rega Institute for Medical Research. Department of Microbiology and Immunology. Clinical and Epidemiological Virology. KU Leuven. Leuven, Belgium | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil | pt_BR |
Affilliation | University of Leuven. Rega Institute for Medical Research. Department of Microbiology and Immunology. Clinical and Epidemiological Virology. KU Leuven. Leuven, Belgium | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil | pt_BR |
Affilliation | Universidade Federal da Bahia. Complexo Hospitalar Universit ario Prof Edgard Santos. Departamento de Pathologia. Salvador, BA, Brasil | pt_BR |
Affilliation | King’s College. Department of Twin Research & Genetic Epidemiology. London, UK | pt_BR |
Affilliation | National Institute of Allergy and Infectious Diseases. Vaccine Research Center. Immunotechnology Section. Bethesda, MD, USA | pt_BR |
Affilliation | 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, | pt_BR |
Affilliation | University of Leuven. Rega Institute for Medical Research. Department of Microbiology and Immunology. Clinical and Epidemiological Virology. KU Leuven. Leuven, Belgium | pt_BR |
Subject | CD95 | pt_BR |
Subject | HTLV-1 | pt_BR |
Subject | Genetics | pt_BR |
Subject | Interferon | pt_BR |
Subject | Leukemia | pt_BR |
Subject | Lymphoma | pt_BR |
Subject | Oncogenesis | pt_BR |