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

Meifang Xu; Fei Wang; Hong Chen; Lin Liu; Wenwen Liu; Yinghong Yang; Qiaoling Zheng; Lihong Zhang; Xiaoxuan Li; Suxia Lin; Shengbing Zang

doi:10.20892/j.issn.2095-3941.2019.0115

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

Cancer Biol Med. 2019 Nov;16(4):743-755. doi: 10.20892/j.issn.2095-3941.2019.0115.

Authors

Meifang Xu¹, Fei Wang², Hong Chen³, Lin Liu⁴, Wenwen Liu⁴, Yinghong Yang¹, Qiaoling Zheng¹, Lihong Zhang⁵, Xiaoxuan Li⁵, Suxia Lin^{5

6}, Shengbing Zang^{5

6}

Affiliations

¹ Department of Pathology, Fujian Medical University Union Hospital, Fuzhou 350001, China.
² Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
³ Department of Pathology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350004, China.
⁴ Department of Pathology, Fujian Medical University, Fuzhou 350004, China.
⁵ Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
⁶ Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.

PMID: 31908892
PMCID: PMC6936234
DOI: 10.20892/j.issn.2095-3941.2019.0115

Abstract

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 (χ² = 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.

Keywords: Angioimmunoblastic T cell lymphoma; FOXO1; differentiation; inactivation.

Publication types

Research Support, Non-U.S. Gov't