FYN – TRAF3IP2 induces NF-κB signaling-driven peripheral T-cell lymphoma

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-κB signaling downstream of T-cell antigen receptor activation. Consistent with a driver oncogenic role, FYN–TRAF3IP2 expression in hematopoietic progenitors induces NF-κB-driven T-cell transformation in mice and cooperates with loss of the Tet2 tumor suppressor in PTCL development. Moreover, abrogation of NF-κB signaling in FYN – TRAF3IP2 -induced tumors with IκB 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-κB targeted therapies in these diseases.