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

Abstract

Angioimmunoblastic T cell lymphoma (AITL) and peripheral T cell lymphoma not-otherwise-specified (PTCL, NOS) have poor prognosis and lack driver actionable targets for directed therapies in most cases. 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 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.

• Authors: Christine S Moon, Clara Reglero, Jose R Cortes, S Aidan Quinn, Silvia Alvarez, Junfei Zhao, Wen-Hsuan W Lin, Anisha J Cooke, Francesco Abate, Craig R Soderquist, Claudia Fiñana, Giorgio Inghirami, Elias Campo, Govind Bhagat, Raul Rabadan, Teresa Palomero, Adolfo A Ferrando
• Journal: Nature cancer (Nat Cancer) Vol. 2 Issue 1 Pg. 98-113 (01 2021) ISSN: 2662-1347 [Electronic] England
• PMID: 33928261 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• NF-kappa B
• Traf3ip2 protein, mouse

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Animals
• Immunoblastic Lymphadenopathy (genetics)
• Lymphoma, T-Cell, Peripheral (genetics)
• Mice
• NF-kappa B (genetics)
• Oncogenes
• Signal Transduction