<i>RHOA</i> G17V induces T follicular helper cell specification and involves angioimmunoblastic T-cell lymphoma via upregulating the expression of PON2 through an NF-κB-dependent mechanism

Abstract

Angioimmunoblastic T-cell lymphoma (AITL) is a malignant hematologic tumor arising from T follicular helper (Tfh) cells. High-throughput genomic sequencing studies have shown that AITL is characterized by a novel highly recurring somatic mutation in <i>RHOA</i>, encoding p.Gly17Val (<i>RHOA</i> G17V). However, the specific role of <i>RHOA</i> G17V in AITL remains unknown. Here, we demonstrated that expression of <i>Rhoa</i> G17V in CD4⁺ T cells increased cell proliferation and induces Tfh cell specification associated with Pon2 upregulation through an NF-κB-dependent mechanism. Further, loss of Pon2 attenuated oncogenic function induced by genetic lesions in <i>Rhoa</i>. In addition, an abnormality of <i>RHOA</i> G17V mutation and PON2 expression is also detected in patients with AITL. Our findings suggest that PON2 associated with <i>RHOA</i> G17V mutation might control the direction of the molecular agents-based AITL and provide a new therapeutic target in AITL.