ID: 239: 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

Abstract

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- α , 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- α 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 × 10−11, n = 669), confirming our hypothesis. Finally, we provide in vivo evidence that CD4+ Fashigh leukemic cells can be eliminated by IFN- α +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.