2020 Theses Doctoral

The FYN-TRAF3IP2 gene fusion drives oncogenic NF-κB signaling in peripheral T cell lymphoma

Kim, Christine Sheila

Angioimmunoblastic T cell lymphoma (AITL) and peripheral T cell lymphoma not-otherwise-specified (PTCL, NOS) have poor prognosis and lack actionable targets for directed therapies in most cases. Here we report the identification of FYN-TRAF3IP2 as a novel highly recurrent oncogenic gene fusion in AITL and PTCL, NOS tumors. Mechanistically, FYN-TRAF3IP2 triggers aberrant NF-κB activity by engaging TRAF6 downstream of T cell receptor signaling. Moreover, 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. Therapeutically, abrogation of NF-κB signaling in FYN-TRAF3IP2-induced tumors via IκB kinase inhibitors delivers strong anti-lymphoma effects in vitro and in vivo. These results formally demonstrate an oncogenic role for FYN-TRAF3IP2 and NF-κB signaling in the pathogenesis of PTCL.