Fyn-Traf3ip2 Induces Nf-Kappa B Signaling-Driven Peripheral T-Cell Lymphoma

Ferrando and colleagues identify FYN-TRAF3IP2 as a recurrent oncogenic gene fusion that promotes angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma not otherwise specified through the activation of NF-kappa B signaling.Angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma not otherwise specified (PTCL, NOS) have poor prognosis and, in most cases, lack driver actionable targets for directed therapies. Here we identify FYN-TRAF3IP2 as a recurrent oncogenic gene fusion in AITL and PTCL, NOS tumors. Mechanistically, we show that FYN-TRAF3IP2 leads to aberrant NF-kappa B signaling downstream of T-cell antigen receptor activation. Consistent with a driver oncogenic role, FYN-TRAF3IP2 expression in hematopoietic progenitors induces NF-kappa B-driven T-cell transformation in mice and cooperates with loss of the Tet2 tumor suppressor in PTCL development. Moreover, abrogation of NF-kappa B signaling in FYN-TRAF3IP2-induced tumors with I kappa B kinase inhibitors delivers strong anti-lymphoma effects in vitro and in vivo. These results demonstrate an oncogenic and pharmacologically targetable role for FYN-TRAF3IP2 in PTCLs and call for the clinical testing of anti-NF-kappa B targeted therapies in these diseases.