Title: A functional FAS polymorphism links CD4 T stem cell memory levels and IFN-induced apoptosis in both healthy controls and Adult T-cell Leukemia patients
Authors: Khouri, Ricardo
Decanine, Daniele
Silva-Santos, Gilvaneia
Theys, Kristof
Li, Guangdi
Silva, Aline Clara
Farre, Lourdes
Bittencourt, Achilea
Mangino, Massimo
Roederer, Mario
Van Weyenbergh, Johan
Issue Date: 2015
Publisher: Academic Press
Host Document: Cytokine vol:76 issue:1 pages:109-109
Conference: 3rd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) location:Bamberg: GERMANY date:OCT 11-14, 2015
Abstract: A functional FAS polymorphism links CD4 T stem cell memory levels and IFN- induced apoptosis in both healthy controls and Adult T-cell Leukemia patients Ricardo Khouri1,2, Daniele Decanine2, Gilvaneia Silva-Santos2, Kristof Theys1, Guangdi Li1, Aline Clara Silva2, Lourdes Farre2, Achilea Bittencourt3, Massimo Mangino4, Mario Roederer5, Johan Van Weyenbergh1,2,* 1Department of Microbiology and Immunology, KU Leuven, Belgium, 2CPqGM-FIOCRUZ, Salvador-Bahia, Brazil,
3HUPES-UFBA, Salvador-Bahia, Brazil,
4Department of Twin Research & Genetic Epidemiology, King’s College London, UK,
5ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH, Bethesda MD, USA
*Corresponding author
Introduction: Adult T-cell leukemia (ATL) is an aggressive, chemotherapy-resistant CD4+ CD25+ leukemia caused by HTLV-1 infection, which usually develops in a minority of patients several decades after infection. Recently, CD4 T stem cell memory (Tscm) cells have been identified as the hierarchical cellular apex of ATL. IFN-a, in combination with AZT, is currently the major treatment option for ATL, but therapeutic success is limited and no bona fide biomarkers for therapeutic failure are currently available. Results: In a prospective study with a five-year clinical follow-up, 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 = 28). We detected a genotype/phenotype interaction for the -670 FAS A/G promoter polymorphism, apoptosis and proliferation in ATL patients. Surprisingly, IFN-induced apoptosis occurred only in carriers of the functional A allele (corresponding to a functional STAT1 binding site), which we experimentally validated in an independent cohort of healthy controls (n = 20). This Fashigh proliferating and chemotherapy-resistant leukemic phenotype is in agreement with the recently discovered CD4 Tscm hierarchical apex of ATL. The same FAS -670 polymorphism also determined CD4 Tscm levels in a genome-wide twin study (p=7 x10-11, n = 460), confirming our hypothesis. Finally, we provide in vivo evidence that CD4+ Fashigh leukemic cells can be eliminated by IFN-a +AZT combination therapy, but not AZT monotherapy. Conclusion: A genetically determined IFN/STAT1/FAS axis underscores the CD4 Tscm ATL model and helps explain the observed in vivo IFN + AZT responsiveness and chemotherapy resistance in ATL patients.
ISSN: 1043-4666
Publication status: published
KU Leuven publication type: IMa
Appears in Collections:Laboratory of Clinical and Epidemiological Virology (Rega Institute)

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