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

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. IFN + 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 (T-SCM) Fas(hi) 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-alpha treatment in short-term culture of primary mononuclear cells from ATL patients (n = 25). Bayesian Network analysis allowed us to integrate ex vivo IFN-alpha 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-alpha. FAS genotype-dependence of IFN-alpha-induced apoptosis was experimentally validated in an independent cohort of healthy controls (n = 20). The same FAS -670 polymorphism also determined CD4 T-SCM levels in a genome-wide twin study (p = 7 x 10(-11), n = 460), confirming a genetic link between apoptosis and T-SCM levels. Transcriptomic analysis and cell type deconvolution confirmed the FAS genotype/T-SCM link and IFN-alpha-induced downregulation of CD4 T-SCM-specific genes in ATL patient cells. In conclusion, ex vivo IFN-alpha treatment exerts a pleiotropic effect on primary ATL cells, with a genetic IFN/STAT1/Fas axis determining apoptosis vs. proliferation and underscoring the CD4 T-SCM model of ATL leukemogenesis.