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

2021; Nature Portfolio; Volume: 2; Issue: 1 Linguagem: Inglês

10.1038/s43018-020-00161-w

2662-1347

Christine S. Moon, Clara Reglero, José R. Cortés, S. Aidan Quinn, Silvia Álvarez, Junfei Zhao, Wen-Hsuan W. Lin, Anisha J. Cooke, Francesco Abate, Craig R. Soderquist, Claudia Fiñana, Giorgio Inghirami, Elı́as Campo, Govind Bhagat, Raúl Rabadán, Teresa Palomero, Adolfo A. Ferrando,

Ubiquitin and proteasome pathways

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. 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-κB signaling.