Inactivation of FOXO1 induces T follicular cell polarization and involves angioimmunoblastic T cell lymphoma

OBJECTIVE: Angioimmunoblastic T cell lymphoma (AITL) is an aggressive form of non-Hodgkin lymphoma derived from mature T cells. However, the underlying pathogenesis of AITL remains unresolved. We aimed to explore the role of FOXO1-mediated signaling in the tumorigenesis and progression of AITL. METHODS: FOXO1 expression was assessed using immunohistochemistry on a total of 46 AITL tissue samples. Retroviruses encoding FOXO1 shRNA were used to knockdown FOXO1 expression in CD4(+) T cells. Flow cytometric assays analyzed the proliferation and survival of FOXO1 knockdown CD4(+) T cells. Furthermore, we performed adoptive T-cell transfer experiments to identify whether inactivation of FOXO1 induced neoplastic follicular-helper T (Tfh) cell polarization and function. RESULTS: Patients with low FOXO1 protein levels were prone to have an advanced tumor stage (P = 0.049), higher ECOG ps (P = 0.024), the presence of bone marrow invasion (P = 0.000), and higher IPI (P = 0.035). Additionally, the survival rates of patients in the FOXO1 high-expression group were significantly better than those in the FOXO1 low-expression group (χ(2) = 5.346, P = 0.021). We also observed that inactivation of FOXO1 increased CD4(+) T cell proliferation and altered the survival and cell-cycle progression of CD4(+) T cells. Finally, we confirmed that inactivation of FOXO1 induces Tfh cell programing and function. CONCLUSIONS: Inactivation of FOXO1 in AITL plays a key role in the tumorigenesis and progression of AITL. We propose that FOXO1 expression could be a useful prognostic marker in AITL patients to predict poor survival, and to design appropriate therapeutic strategies.