Role of Rhoa G17V in Cell Migration and Transformation in Angioimmunoblastic T-Cell Lymphoma

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive form of peripheral T-cell lymphoma derived from the malignant transformation of follicular helper T-cells (TFH), frequently associated with autoimmune disease and characterized by resistance to chemotherapy and poor prognosis. A recurrent RHOA G17V mutation in the RHOA small GTPase gene is characteristically present in 70% of AITL cases, frequently in association with loss of function mutations in the Tet2 epigenetic regulator. Expression of Rhoa G17V in CD4⁺ T cells in a conditional Rhoa^co-G17V/+ knockin mice induces TFH cell specification and increased proliferation. A pathogenic role for Rhoa G17V in cooperation with loss of Tet2 is demonstrated by the development of AITL in a CD4⁺ specific Rhoa G17V Tet2 knockout mice. However, the specific effector mechanisms driving TFH specification and T-cell transformation downstream of Rhoa G17V remain largely unknown. Here we demonstrate a novel role for Rhoa G17V as a modulator of signaling cascades initiated by sphingosine-1-phosphate (S1P), an important lipid mediator of lymphocyte trafficking. Specifically we show that expression of Rhoa G17V results in impaired S1P receptor internalization with the consequent up-regulation of S1P-dependent signaling pathways. In addition, and of potential therapeutic relevance, targeted inhibition of S1P signaling in Tet2^-/-RHOA G17V mouse AITL cells induces apoptosis and reduces tumor load in vivo. In all, these results uncover a previously unrecognized role for S1P signaling downstream of Rhoa G17V in AITL tumor cell migration and survival, and support the role of S1P receptors as potential therapeutic target for the treatment of this disease.