A genetic IFN/STAT1/FAS axis determines CD4 T stem cell memory levels and apoptosis in healthy controls and Adult T-cell Leukemia patients

dc.creatorCunha, Antonio Ricardo Khouri
dc.creatorSantos, Gilvanéia Silva
dc.creatorDierckx, Tim
dc.creatorMenezes, Soraya Maria
dc.creatorDecanine, Daniele
dc.creatorTheys, Kristof
dc.creatorSilva, Aline Clara
dc.creatorVallve, Maria Lourdes Farré
dc.creatorBittencourt, Achilea Candida Lisboa
dc.creatorMangino, Massimo
dc.creatorRoederer, Mario
dc.creatorVandamme, Anne-Mieke
dc.creatorWeyenbergh, Johan Van
dc.date2018-04-16T14:19:05Z
dc.date2018-04-16T14:19:05Z
dc.date2018
dc.date.accessioned2023-09-27T00:12:06Z
dc.date.available2023-09-27T00:12:06Z
dc.identifierKHOURI, 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.
dc.identifier2162-4011
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/25855
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8898464
dc.descriptionFonds Wetenschappelijk Onderzoek (G0D6817N) CNPq-FAPESB (PRONEX) VLAIO (PhD scholarship TD) Onderzoeksraad, KU Leuven (IRO) Onderzoeksraad, KU Leuven (Vaast Leysen Leerstoel)
dc.descriptionAdult 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.
dc.formatapplication/pdf
dc.languageeng
dc.publisherTaylor & Francis
dc.rightsopen access
dc.subjectCD95
dc.subjectHTLV-1
dc.subjectGenética
dc.subjectInterferon
dc.subjectLeucemia
dc.subjectLinfoma
dc.subjectOncogênese
dc.subjectCD95
dc.subjectHTLV-1
dc.subjectGenetics
dc.subjectInterferon
dc.subjectLeukemia
dc.subjectLymphoma
dc.subjectOncogenesis
dc.titleA genetic IFN/STAT1/FAS axis determines CD4 T stem cell memory levels and apoptosis in healthy controls and Adult T-cell Leukemia patients
dc.typeArticle


Este ítem pertenece a la siguiente institución